Put a label (claim) on it

Abstract

Relevance:

Non-surgical contraceptives or sterilants need regulatory approval to be sold for that use. This approval process gives veterinarians the information required to assess the benefits and risks of each product, and to provide comprehensive information on the required dose, method and duration of use, safety and effectiveness.

Aim:

This article reviews the information that must be developed and provided to regulatory agencies worldwide, with a focus on the European Union and the United States, in order to achieve regulatory approval.

Processes:

The main components of developing a drug include developing extensive information on the safety and effectiveness of the product, and also the safety to the environment and to humans handling and administering the drug. Most importantly, a robust method of manufacturing both the drug itself and the formulated drug product (pill, liquid implant or injection) must be developed to assure quality and consistency in each batch. This information is then compiled and submitted to regulatory agencies; in the United States, this includes the Food and Drug Administration, the United States Department of Agriculture and the Environmental Protection Agency, and, in Europe, the European Medicines Agency.

Challenges:

Because of the unique nature of non-surgical contraceptives for use in cats and dogs, particularly the desire to have these products last over multiple years, there are special challenges to their regulatory approval that are discussed in this review.

Introduction

Veterinarians use drugs every day and are skilled at reading labels and understanding nuances of how various common drugs affect their patients. Drug labels and package inserts contain information to help guide veterinarians about how to use drugs safely to have the desired effect in their patients. But what does it take for a manufacturer to get regulatory approval – be it from the US Food and Drug Administration (FDA), Environmental Protection Agency (EPA) or European Medicines Agency (EMA) – and generate the information that is included with each drug?

The label is usually the result of 5–10 years of intense research and development. For drugs for cats and dogs, the cost of getting an approval can range from approximately USD $8–12 million. Why so long and so much? The basic reason is that each drug needs to be rigorously tested to assure that it is safe and effective for the indication, and that each time a veterinarian dispenses the drug, it is exactly what it is supposed to be – essentially the same concentration, potency and bioavailability in every pill or liquid dose.

Regulatory requirements for approval of contraceptives for cats and dogs differ depending on the mechanism of action of the contraceptive approach, as well as the country in which approval is sought. The purpose of this article is not to serve as a detailed guide for regulatory approval of specific products, but instead to give an overview of the regulatory processes and issues.

Regulatory requirements worldwide generally fall into three major categories for companion animal products:

• Effectiveness;

• Safety;

• Manufacturing (also called chemistry, manufacturing and controls, or ‘CMC’).

In addition, products are evaluated for their possible environmental impact and the safety of humans handling the product. (Note that there are additional requirements for products intended for animals used for food – meat and milk – and discussion of these requirements is beyond the scope of this article.)

The company developing the product (the ‘sponsor’) is responsible for submitting all information required for review by regulatory authorities prior to approval. In addition, most regulatory bodies require payment of significant fees (hundreds of thousands of dollars) as part of their review process.

This article specifically considers the regulatory process for products for companion animal species (cats and dogs). However, non-surgical fertility control products have been approved for wildlife as well (see Table 1, page 788); when appropriate, examples from other species are presented.

Table 1

Animal contraceptives approved in the US (by the FDA or EPA) and EU (by the EMA) between 2003 and 2013

Species	EPA	FDA	EMA
Dogs	–	Zinc gluconate neutralized with arginine (Zeuterin; Ark Sciences) for males (also known as Neutersol)	Deslorelin acetate implant (Suprelorin; Virbac) for males Azagly-nafarelin acetate implant (Gonazon; Merck) for females*
Cats	–	–	–
White-tailed	GnRH–hemocyanin protein conjugate (Gonacon; National Wildlife Research Center, USDA-APHIS Wildlife Services Program) for females	–	–
Wild horses	GnRH–hemocyaninprotein conjugate (Gonacon; National Wildlife Research Center, USDA-APHIS Wildlife Services Program) for females	–	–
	Porcine zona pellucida vaccine (ZonaStat-H; The Science and Conservation Center) for females
Canada geese, wild pigeons and ducks	Nicarbazin Nicarbazin (OvoControl; Innolytics)	–	–

EPA = Environmental Protection Agency; FDA = Food and Drug Administration; EMA = European Medicines Agency; USDA-APHIS = United States Department of Agriculture’s Animal and Plant Health Inspection Service

*

Gonazon (developed by Intervet and acquired by Merck) is no longer on the market

Effectiveness

For a contraceptive, the sponsor must prove that the drug will suppress fertility in a particular species for a specific length of time. This is called a ‘claim’ or ‘label indication’. What claims might the label of a contraceptive product contain? The claims are based on the effectiveness of the product and are backed up by clinical data in the relevant species, collected from both laboratory and field studies. Regulatory agencies use the proposed claim to determine what type of data will be needed to support approval of the product. Design of the effectiveness claims and clinical trials to prove them must be coordinated with a clear strategy so that, at the end of the development process, the market is defined and communication with veterinarians can be effective.

For contraceptives and fertility control drugs, claims must include the species in which the product will be used (eg, cat or dog) and might include:

• Definition of the population for which the product is useful (eg, for male and female cats over 6 months of age);

• How quickly the product will show its effect (eg, for vaccines, how long is it from the initial injection and any follow-up boosters to full contraceptive effect?);

• The length of time for which the product is proven to work (duration of effect);

• The potential reversibility of the treatment (eg, will cats regain their ability to breed when treatment is discontinued? If so, in how long a time?);

• How the product is used (injections, oral dosing, implants);

• Schedule of use (eg, once every 6 months);

• Dose (if applicable).

For both cats and dogs, it is important for a developer of a contraceptive product to make sure that the clinical trials are conducted in the widest possible population in order to achieve the broadest claim. For example, cats of various ages and breeds should be used for the clinical work, as some veterinarians might want to use a contraceptive in adult cats, while others will be interested in treating kittens, should owners not want their female cats to exhibit even one estrus.

Duration and potential reversibility of effect need to be measured in clinical trials. If the label claim is intended to be ‘effective contraception for a year’, studies of at least a year’s length will be necessary. How will effectiveness be proven if the label claim is permanent sterilization? Multi-year trials over the lifetime of a pet are not practical, and so it is unlikely that such a label claim would be realistic unless the product produced actual tissue destruction of the testicles or ovaries. One strategy that companies developing these types of products might adopt is to initiate launch of the product with a label defining duration as 12 months, and then continue the studies, filing label extensions to increase the duration claim, if possible, or to demonstrate that repeat treatment extends the duration of effect.

What about products that may have a variable onset of and decline in effectiveness, such as a gonadotropin-releasing hormone (GnRH) vaccine or porcine zona pellucida vaccine that may provide 6 months of contraception in one animal and 2 years in another? Even in the best of cases, individual animals in a clinical trial will probably have to be followed for at least a year, making clinical efficacy trials long, labor intensive and expensive. If claims for continued effects based on booster immunizations are desired, multi-year trials may be needed.

One of the major reasons pet owners spay or castrate their cats is because the animals are exhibiting unwanted sexual behaviors; for example, estrous behavior in females and territorial marking/spraying, roaming, inter-cat aggression and yowling in male cats. To include label claims on their contraceptive products such as ‘use of this product will reduce sexual behavior’, sponsoring companies may have to conduct behavioral evaluations. Even if it can be demonstrated that the proposed contraceptive suppresses serum sex steroids (eg, testosterone in male cats), it is unlikely that regulatory authorities will allow the use of this surrogate endpoint to make behavior claims. It is interesting to note that the package insert for Zeuterin™ (Ark Sciences), an injectable sterilant for male dogs approved by the FDA without behavior studies being required, includes the following statement: ‘As with surgical sterilization, secondary male characteristics (roaming, marking, aggression, or mounting) may be displayed.’ ¹

Safety

Target animal safety

Contraceptive products should be demonstrated to be safe for the treated animals, but what exactly does ‘safe’ mean? For regulatory approval, safety is proven by conducting a study in the ‘target’ animal (ie, the species in which the product will be used). Ideally the resulting study shows that the normal dose and higher doses, sometimes given multiple times, cause limited or no adverse effects. The study must include a reasonable number of animals of appropriate ages. A regulatory guideline has been developed that is used in several countries as the standard for designing these safety studies. The Veterinary International Cooperation on Harmonization (VICH) guidelines for target animal safety suggest using laboratory cats and dogs, which can be observed closely during the study. ² The guideline requires the use of four males and four females per group and suggests inclusion of 0, 1, 3 and 5 x groups; that is, cats or dogs in the study should be treated with a placebo, the intended dose, or 3 x or 5 x that dose, which can help define a safety margin.

The guidelines say that safety studies should be conducted for three times the duration of the proposed use. For example, if an antibiotic is prescribed to be used for 10 days, the safety study should be conducted for 30 days. For potential cat contraceptives that are designed for multi-year effectiveness, if this guideline were strictly followed, studies would be required to run for many years, which is impractical. Sponsors will need to work with the regulators to help design a safety study that adequately addresses long-term safety without requiring studies that are so long as to be impossible. Regulatory authorities are likely to work with sponsors to find a way to adequately assess long-term safety of potential contraceptive drugs.

During the safety study, animals are observed for any behavioral changes, and injection or implant sites are monitored for any signs of irritation, pain or inflammation. Clinical pathology parameters such as hematology, urinalysis and serum chemistry are monitored, and at the end of the target animal safety study, animals are euthanized and full necropsies performed. Gross pathology and histopathology are required, along with other, more specialized measurements depending on the product. All procedures must be done under good laboratory practice (GLP) regulations. Conduct of this study can take a year and up to USD $500,000 or more, depending on the species and duration of the experiment.

Many agencies also require ‘field safety’ to be evaluated in a wider population of breeds and ages in a ‘real world’ situation. To satisfy this requirement, safety information (adverse events) is required to be documented and reported to regulatory authorities. Finally, after a product is approved, the FDA, EMA and other regulatory bodies worldwide require post-approval monitoring for safety (‘pharmacovigilance’). This means that the sponsor is required to establish a way to collect reports of problems or side effects seen in animals treated with the product, and these adverse events must be reported regularly to regulatory agencies to monitor safety in the actual population of cats and dogs being treated with the product.

Human safety

In all cases, the safety of the person handling drugs or immunocontraceptives is a concern. If a vaccine or other injectable contraceptive has a long-lasting or permanent effect, the people administering the product will be at risk for self-injection and compromise of their own fertility, and the labeling will have to reflect these issues. It is likely that some types of products could be restricted to use by veterinarians or trained personnel only. For example, the label for Gonacon™ (regulated by the EPA for use in adult female white-tailed deer, wild horses and wild burros) states: ‘Restricted use pesticide: due to non-target injection hazard. For the use by USDA-APHIS wildlife services or state wildlife management agency personnel or persons working under their authority.’ ³

Exposure to toxic substances such as chemotherapeutic agents, and worries about HIV and other infectious agents in human blood, have prompted a number of companies to develop injection technology that protects the person giving the treatment. It should be possible for some type of device to be developed for veterinary contraceptive injections that would similarly protect the veterinarian or technician giving the injections to animals. This could become an issue in the development of immunocontraceptives that may be entering clinical trials. Veterinary clinics could be reluctant to participate in a trial in which their staff members may be exposed to an experimental contraceptive. Certainly it would decrease the risk of non-participation if the experimental immunocontraceptive were to be delivered via a device that minimized the possibility of human exposure.

Environmental assessment

Particularly for the US EPA, but also for other regulatory agencies, the environmental impact of contraceptives must be evaluated, and the scope of this assessment will depend on the specific product and may include data on field use. Oral, implanted or injected drugs that are given to individual pets, and therefore have limited effects on the environment generally, will receive a waiver from conducting an extensive environmental assessment. However, in the case of a product used for unowned, free-roaming or feral animals, field use data may be needed.

Over the years, various research approaches to contraception for wildlife and feral animals have included attempts at designing baits to place in the area where feral animals live. Baited contraceptives for cats and dogs are very unlikely to be approved, since the probability of ‘off-target’ animals or humans, including children, being exposed is high. Development efforts are under way to achieve a species-specific product in which only the target species will respond to or be able to access the bait, but species specificity is a significant obstacle.

Manufacturing

In the case of drugs registered by the FDA, EMA and EPA, manufacture of the active pharmaceutical ingredient and the formulated product must be conducted under good manufacturing practice (GMP) regulations. For immunocontraceptives, regulated by the FDA or EPA (eg, ZonaStat-H™ for feral horses), similar quality standards apply. This is to demonstrate to the veterinarian and the public that strict quality standards are used in the manufacturing of the product, which assures its safety and effectiveness will be essentially the same as that demonstrated during the drug development process.

Probably the least appreciated, but most important step in bringing a product through commercial development successfully is developing a formulation – that is, the active ingredient in combination with excipients that help keep the product stable, in solution, buffered appropriately, etc. In terms of stability, the active drug or antigen has to remain intact over a reasonable shelf-life. It must be determined if the product needs special storage requirements (such as refrigeration), which may impact practical use in the field. The formulation must be non-irritating to tissue when injected or implanted, especially if multiple applications are required (eg, boosters or repeat implants).

Product sterilization methods must be developed that are effective and do not degrade the antigen or drug. If an implant is being developed, release rates of the active ingredient need to be demonstrated under a variety of conditions, and if the product is to be an injectable, syringeability must be good – that is, it must not be too thick to pass through a needle small enough to inject a cat or dog.

Once a few possible formulations have been defined that meet the aforementioned criteria, one ‘lead’ formulation is selected. For this formulation, effectiveness must be confirmed in a reasonable number of animals. For a contraceptive product, these tests can take 6 months to a year, assuming the product claim is for that length of time. Depending on the product, the process of defining a final formulation can take several years and cost several million dollars. Separate formulations may be needed for cats and dogs, especially for immunocontraceptives requiring adjuvants in order to be effective.

For manufacturing the final product, many requirements need to be fulfilled. For example, packaging, sterility, reproducibility from lot-to-lot, stability under a variety of handling conditions, cleaning requirements and labeling need to be worked out. The impact of manufacturing on the environment must be defined. Manufacturing must be scaled up to meet demand once the product is launched. Selecting the right manufacturing process and toll manufacturer (contract manufacturers used if a company does not manufacture its own products) can make or break a product and its ability to meet regulatory requirements.

The costs and timing of meeting the requirements and getting successfully through the approval process with the FDA, EPA, EMA and other regulatory agencies worldwide vary depending on the complexity of the product. Experienced companies know that assembling the necessary documentation for manufacturing can take a minimum of 2–3 years and carries a multi-million dollar price tag. In some cases, a factory needs to be built, requiring large capital investment.

Time frame for regulatory approval

How quickly regulatory approval can follow after submission of all required documentation varies widely depending on the country, the product and the quality of the submission. Working closely with a given regulatory body during the development of a drug or immunocontraceptive can speed up the process in some cases, but it would not be unusual for the entire approval process, including required studies and regulatory review, to take up to 5–10 years; the process could be longer for long-acting products. Nonetheless, products for domestic species (dogs) and wildlife have been approved, as shown in Table 1, which lists products that received regulatory approval between 2003 and 2013. The list does not include older products based on progesterone or related compounds.

Since 2003, we have seen only three products (Suprelorin, Gonazon™, Zeuterin™) achieve regulatory approval for contraception or permanent sterilization in dogs, and no products have been approved for cats. Gonazon was approved for use in female dogs in the EU and not commercialized. Suprelorin is approved for use in Australia, New Zealand and the EU, but only for male dogs. Zeuterin, which was originally approved by the FDA under the brand name Neutersol™, is on the market in the US for male dogs; the product was also approved in several Latin American countries under the brand name EsterilSol, and it has been re-launched and is on the market in the US as Zeuterin.

Conclusions

There is a long road from demonstrating that a certain contraceptive approach can suppress fertility in a cat or a dog and achieving regulatory approval for a product that can be marketed. For each potential product, the regulatory path is unique. The scarcity of cat and dog contraceptives approved for use reflects both the lack of research into new approaches by pharmaceutical companies and how difficult the regulatory hurdles can be. One can hope that these few approved products have pioneered the way for future breakthroughs for feline and canine contraception.

Key points

• Worldwide regulatory requirements for companion animal products fall into three major categories: effectiveness, safety and manufacturing. In addition, products are evaluated for possible environmental impact and safety for humans handling the product.

• The European Medicines Agency (EMA) regulates pharmaceutical products for animals in the European Union. In the US, the Food and Drug Administration (FDA) and the Environmental Protection Agency (EPA) regulate depending on the nature of the product. Due to the high standards for safety, effectiveness and manufacturing, it may take 5–10 years and USD $8–12 million to achieve regulatory approval.

• Veterinarians in some countries can legally prescribe or use drugs ‘off-label’, including having the drug compounded. Compounding pharmacies are not required to assure safety, effectiveness or quality of drugs they dispense.