Exploration of developmental approaches to companion animal antimicrobials: providing for the unmet therapeutic needs of dogs and cats
Abstract
AAVPT Workshop White Paper Committee. Exploration of developmental approaches to companion animal antimicrobials: providing for the unmet therapeutic needs of dogs and cats. J. vet. Pharmacol. Therap.33, 196–201.
The American Academy of Veterinary Pharmacology and Therapeutics (AAVPT) and the United States Pharmacopeia (USP) co-sponsored a workshop to explore approaches for developing companion animal antimicrobials. This workshop was developed in response to the shortage of antimicrobials labeled for dogs and cats, as there is a shortage of approved antimicrobials for the range of infectious diseases commonly treated in small animal practice. The objective of the workshop was to identify alternative approaches to data development to support new indications consistent with the unmet therapeutic needs of dogs and cats. The indications for currently approved antimicrobials do not reflect the broader range of infectious diseases that are commonly diagnosed and treated by the veterinarian. Therefore, the labels for these approved antimicrobials provide limited information to the veterinarian for appropriate therapeutic decision-making beyond the few indications listed. Industry, veterinary practice, and regulatory challenges to the development of new antimicrobial indications were discussed. The workshop resulted in short- and long-term recommendations. Short-term recommendations focus on the use of additional data considerations for product labeling. Long-term recommendations center on legislative or regulatory legal initiatives. The workshop recommendations will need collaboration from industry, academia, and regulatory authorities and a legal shift in the drug approval and availability processes.
Introduction
The American Academy of Veterinary Pharmacology and Therapeutics (AAVPT) and the United States Pharmacopeia (USP) co-sponsored a workshop to explore developmental approaches to companion animal antimicrobials. The meeting was held in Rockville, Maryland on October 23 and 24, 2008. The AAVPT has historically played a pivotal role to bring together representatives from industry, government, and academia to consider, and attempt to resolve, important issues relating to availability and use of medications for veterinary medicine. This workshop was developed because AAVPT, USP and the Center for Veterinary Medicine recognized the need to improve the availability of approved antimicrobials for dogs and cats. The sponsors of the workshop are aware of the shortage of approved antimicrobials for the range of infectious diseases commonly treated in small animal practice. The objective was to identify alternative approaches to data development to support new labeling indications consistent with the unmet therapeutic needs of companion animal medicine, specifically dogs and cats. Participants in the workshop included representatives of the FDA Center for Veterinary Medicine, academic institutions, private practice, and industry, who shared the common goal of ensuring the future availability of approved safe and effective antimicrobials for dogs and cats.
Preamble
The approach to development of effectiveness data in the last 10 years has resulted in approval of antimicrobials with a limited scope of indications in dogs and cats. From 1997 to 2008, five antimicrobials were approved for dogs (orbifloxacin, marbofloxacin, difloxacin, cefpodoxime, and cefovecin) and three antimicrobials were approved for cats (orbifloxacin, marbofloxacin, and cefovecin). The infectious disease indications for these antimicrobials were limited to secondary superficial pyoderma and urinary tract infections in dogs, and skin infections (wounds and abscesses) in dogs and cats. The approved indications do not reflect the broader range of infectious diseases that are commonly diagnosed and treated by the veterinarian. Therefore, the approved antimicrobials currently available provide limited information to the veterinarian for appropriate therapeutic decision-making beyond the restrictions of the labeled indications.
Veterinarians can legally use human antimicrobials in companion animal practice, as defined in 21 CFR 530-Extralabel Drug Use in Animals. However, extra-label use of human drugs in companion animals typically lacks the underlying scientific evidence to support the appropriate dosage regimen for safe and effective use, when compared with the evidence for a product approved for the indication.
The challenge before the workshop participants was to consider alternative approaches to accumulate ‘substantial evidence’ that a drug is effective for treating a specific infection. These approaches involve an understanding of the drug, the infectious disease, and the patient population – with the goal of providing recommendations for development of evidence-based, FDA-approved indications that promote responsible use of antimicrobials while meeting the broader therapeutic needs of companion animals.
Scope of meeting
The goal of the workshop was to explore alternative approaches for developing scientifically valid evidence to support FDA approval of a broader range of antimicrobial drug indications consistent with the unmet therapeutic needs of companion animal (dog and cat) medicine. The discussions identified the common infectious diseases in dogs and cats; described the challenges of drug development faced by industry in this therapeutic area; and reviewed the currently approved FDA antimicrobial drugs, the legal requirements for drug approval, and the essential information needed in labeling for safe and effective use of companion animal antimicrobials by the practitioner.
To facilitate conversation and incorporate input from all participants, the workshop utilized small break out groups with various antimicrobial drug scenarios used as thought-provoking measures. The specific summaries from each break out group for each scenario presented may be viewed at the AAVPT website –http://www.aavpt.org/AntimicrobialWorkshop2008.shtml.
Summary of meeting
The Antimicrobial Workshop was open to the public and was well-attended, with participants including academicians, industry representatives, regulatory scientists, and practicing clinicians. To balance different perspectives in the development of new therapeutic approaches, the workshop program was designed by representatives from all three major AAVPT constituent groups – academia, industry, and regulatory agency. The workshop was opened by providing an overview of the program, objectives and expectations, an historical regulatory perspective, and an introduction into challenges for the development of antimicrobials from the industry perspective. The participants discussed ways to improve the current labeling of antimicrobials to help determine dose, dosage interval, and duration for new indications and/or additional species.
The practitioner’s dilemma
Veterinary practitioners presented the criteria they use for selection of an antimicrobial, dose, dosage interval, and duration under actual conditions of use, as well as how they determine the product’s safety when used in an extra-label manner. Companion animal practitioners discussed common infectious diseases currently recognized in veterinary practice. From a feline practitioner’s view, the most commonly observed anatomic infection sites include urinary tract, skin, and the upper respiratory tract (including otitis media). For many feline indications, there are currently no FDA-approved antibiotics. Consequently, feline practitioners commonly have to use antimicrobials in an extra-label fashion and have to accept the additional risk over having an approved product for the indication. Other practitioners also indicated that they frequently must rely on unapproved human-label drugs for treatment of disease for which there are no approved indications.
As part of the clinical perspective session, a summary of quantitative microbiological findings from laboratory survey data was presented, comparing three different veterinary diagnostic laboratories across the US. Although there were some differences across the laboratories, it was apparent that the most common anatomic sites for sampling veterinary patients were urine, ear, and skin. Although this sampling trend could be inferred to mean that these are the most common sites of infection, it is also possible that these sites are the easiest sites to sample and therefore are relatively over-represented. The microbiologic laboratory presentation also showed that there is a trend toward increasing resistance to many currently approved drugs. The lack of approved antimicrobials for these emerging resistant pathogens is a problem for practitioners and presents an additional challenge for drug sponsors.
Challenges for the industry
The animal health industry presented their obstacles and threats. They are confronted with major challenges that have resulted in a decrease in FDA-approved antimicrobial drugs for companion animals. The pipeline is shrinking, as human pharmaceutical investment in new antimicrobial chemical entities continues to decline. Human generics compete in the market place against exclusive veterinary products, and the return on investment in this therapeutic area is negative because development time and cost investments exceed sales potential.
The animal drug development pipeline is intimately linked to the human pharmaceutical discovery pipeline. As the human antimicrobial discovery pipeline has contracted, development of veterinary drugs in this therapeutic sector has similarly declined. Projecting future development in 2004, new antibacterial agents constituted six of 506 drugs disclosed in the developmental programs of the largest pharmaceutical and biotechnology companies (Spellberg et al., 2004). Accordingly, this is reflected in the 56% decrease in approval of new antibacterial agents, as reported by FDA.
Historically, patent term protection as a legal tool has allowed time for recovery of some of the discovery and development costs for pioneer molecules. Separately from this, marketing exclusivity is a legislated provision that is intended to provide incentive for continued research and development (R&D) investment on drug products. Marketing exclusivity is granted for 5 years on first animal/first claim for a drug product containing a new chemical entity and 3 years on additional label claims or next animal species for the drug product. Dissecting R&D investment more closely, manufacturing, effectiveness, and safety are the three main cost categories for companion animal pioneer drug development. In the context of extra-label use under the Animal Medicinal Drug Use Clarification Act (AMDUCA), the R&D return on investment in veterinary pioneer drugs and labeling claim extensions is uniquely vulnerable to deflated market pressure from human generic drugs. AMDUCA allows extra-label drug use in companion animals. This vulnerability to human generic pressure creates a clear disincentive for continued R&D investment in this veterinary therapeutic sector.
Re-invigoration of this therapeutic area is a complex problem with no easy solution. Time to market is a main driver of return on R&D investment. For the purposes of this discussion in the workshop, the focus was specifically on the pivotal multi-site GCP field study and measures to decrease the time to market. The multi-site GCP field study is the largest document and data set carrying the highest cost and time investment within the Effectiveness Technical Component. Managing this technical section efficiently is a key to reducing the timeline to drug approval and market authorization.
The existing regulations
There was focused discussion on the development of effectiveness data to support approval of NADAs or new indications for previously approved NADAs. The Code of Federal Regulations (21 CFR 514) defines the broad legal requirements for substantial evidence of effectiveness to support new animal drug approval. The regulations state that evidence of effectiveness can be provided by ‘a study in a target species, study in laboratory animals, field study, bioequivalence study, or an in vitro study.’ The regulations also state that the types of studies ‘that are intended to provide substantial evidence of the effectiveness of a new animal drug may include, but are not limited to, published studies, foreign studies, studies using models, and studies conducted by or on behalf of the sponsor.’
The use of PK/PD information
There were extensive discussions about the extent to which ‘substantial evidence’ can include pharmacokinetic–pharmacodynamic (PK/PD) information to support antimicrobial label claims for dogs and cats. Pharmacokinetic–pharmacodynamic approaches should be viewed as a tool for modifying the clinical data needed to support application approval. Situations in which PK/PD alone may be used to support a label indication are rare, and primarily involve this tool for bridging to existing clinical safety and effectiveness data. However, with the exception of locally acting drugs whose effects are independent of systemic drug exposure, PK/PD data answer important therapeutic questions allowing sponsors to reduce substantially the size of their clinical field trials. Despite its potential shortcomings, some argued that the PK/PD approach may be no less indicative of a successful therapeutic outcome than the active control clinical trial, where studies are conducted without a placebo concurrent (negative) control to monitor the rate of spontaneous cure.
Assumptions to be established: When generating these PK/PD data, it is essential that sponsors define their foundational assumptions, provide information to support those assumptions, and indicate where additional data are to be collected. If the drug is from a well-described class of antimicrobial compounds, the sponsor can provide existing information (e.g., published references) to support whether the antimicrobial actions are time- or concentration-dependent as well as to define the PK/PD targets (e.g., AUC/MIC ratios, % time above MIC, or Cmax/MIC ratios). Properties of a class of antimicrobials may be applied to new drugs developed that fall into the same class. However, if the sponsor is seeking a claim for which the bacteria targeted are substantially different from the original claim, or for multiple bacteria, evidence should be provided to show that PK/PD criteria apply to all bacteria listed on the indication. When PK/PD mechanisms need to be defined, the Workshop discussion included numerous examples of animal models being extremely beneficial in the effort to enhance the understanding of antimicrobial drug activity (e.g., neutropenic mouse model, rat thigh model).
If a new indication is pursued for a different tissue in the same species, evidence should be provided that sufficient drug concentrations (free drug) can be obtained in the extracellular tissue to support a therapeutic effect. For example, if a drug is approved for skin/soft tissue, and a sponsor seeks to expand the label to include infections in the bone, respiratory tract, prostate, etc., evidence for drug penetration to those tissues at a level similar to or higher than skin or soft-tissue should be provided. For many compounds, an extensive library of published data is available to support assumptions on tissue partitioning characteristics of drugs. Information about the drug’s protein binding is essential for establishing the relationship between plasma drug concentration and tissue concentration.
As part of the PK/PD discussion, there was a round-table session on the use of PK/PD data in support of effectiveness. The topics included mechanisms potentially appropriate for the determination of the exposure–response relationship (other than clinical trials), including the use of kill curves, hollow fiber data, and other in vitro methods for the establishment of a PK/PD target.
Exceptions to traditional assumptions: There are also situations when PK/PD assumptions may not be well defined. For example, multiple studies may be needed to describe the mechanism of action and/or pharmacodynamics of novel compounds. If a drug acts in vivo via mechanisms that are different from traditional in vitro bactericidal/bacteriostatic mechanisms, the sponsor should provide evidence to describe these other mechanisms.
For an indication targeted toward organisms for which PK/PD criteria have not been well-defined (e.g., fastidious organisms, blood-borne pathogens, tick-borne diseases) microbiologic data (e.g., MIC data) and/or PK/PD parameters may not be established. In these instances, PK/PD approaches may have limited application and establishing an indication will require more reliance on disease models and clinical study results.
The USP approach
The United States Pharmacopeia representatives provided an overview of the development of USP veterinary clinical drug information monographs that provide evidence- and consensus-based support for the use of antimicrobials in animals, utilizing a public process that includes evaluating the strength of evidence. They also described efforts by the organization and volunteers to build a comprehensive veterinary database, which could be used for drug and dose selection in veterinary practice. Details of the USP presentation are included on the AAVPT website – In 2009, USP transferred all the Veterinary Clinical Drug Information Monographs to AAVPT and they are available on the AAVPT web site at http://www.aavpt.org/USPmonographs.shtml./AntimicrobialWorkshop2008.shtml. http://www.aavpt.org/antimicrobialworkshop2008.shtml.
Clinical trial design
There was a presentation and extensive discussion on alternative clinical trial designs, as well as alternatives to clinical trials (such as case studies, cohort studies, laboratory studies, etc.). Alternative clinical trial designs were discussed for three additional antimicrobial therapeutic areas with unmet needs: urinary tract infections, hemoparasites, and periodontitis/gingivitis. In these discussions, the possible differences in the data required to show substantial evidence of effectiveness for a new molecular entity vs. a new indication for an already approved compound were considered.
One session of the workshop was devoted to the discussion of the challenges of selecting control groups for clinical studies, including the use of historical control data in the drug approval process. To overcome the limitations of a study that uses a historical control (which lacks a parallel randomized comparator group), a Bayesian approach was introduced. The Bayesian approach provides the opportunity to compare historical and current data using a possibly smaller control group to augment the historical control information. This method incorporates historical control information as a prior belief (prior distribution) and then updates that belief with new data. Once the study is finished, the data from the control group (assuming they are comparable with the historical data) are combined with the prior distribution through a Bayesian analysis, resulting in a ‘posterior distribution’ for the control group, and the posterior distributions for the control and treated groups are then compared for inference. Other topics in the statistics session included a discussion of the use of multiple indications in a single clinical trial, and further discussions on various types and considerations for selecting control groups for a clinical trial.
Workshop recommendations
Short- and long-term approaches to deal with the challenges arose from the discussions. Short-term approaches focused on additional data considerations for product labeling and were considered to be more readily implemented within the immediate stakeholder group. Long-term approaches centered on grass roots, legislative or regulatory legal initiatives and were considered broader in scope and more complex to implement. These long-term initiatives will need to involve a wider group of stakeholders, which would necessitate a fundamental legal shift in the drug approval and availability processes and thus, require an inherently long lead time for implementation.
The following recommendations were proposed as mechanisms to increase the availability of registered antimicrobials for dogs and cats by increasing initial submissions, and for expanding the indications and scientifically valid information (e.g., target species PK/PD information) on companion animal antimicrobial labeling and in the Freedom of Information summary. However, discussion of the legal feasibility of the recommendations was beyond the scope of the workshop.
- 1
Increase first-time approvals for new antimicrobials for dogs and cats:
- a)
For the approval of a new antimicrobial for dogs and cats, certain data are essential for initial consideration of a new antimicrobial for dogs and cats. These data include:
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Pharmacokinetic data in the target species (PK).
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Safety studies in the target species (Target Animal Safety – TAS).
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Description, if known, of the pharmacokinetic–pharmacodynamic (PK/PD) behavior of the drug to be considered or for the drug class.
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Microbiologic activity of the drug, from collection of field isolates for the pathogens to appear on the label. Microbiologic data should be generated using approved public standards, such as those published by the Clinical Laboratory Standards Institute (CLSI).
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Determination of final formulation and dose.
- •
- a)
- b)
Once the above criteria (1.a.) are met, effectiveness of the new antimicrobial can be derived through a combination of other procedures. Drug sponsors should be encouraged to contact the FDA-CVM for guidance in advance of planning their additional studies or accumulation of new data that may be used for a label indication. These data may include:
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Confirmatory clinical field trial (traditional approach) using appropriate active control and multiple study sites.
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Pharmacokinetic–pharmacodynamic data (PK/PD) indicating that the drug meets accepted targets (e.g., T>MIC, AUC/MIC) for the MIC of pathogens causing the infection. (It should be emphasized that the PK/PD data alone cannot be used in support of effectiveness, which should always be confirmed in a field study conducted under clinical conditions of use.)
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Data from foreign clinical trials that have used the same formulation and dose.
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Support from published literature indicating that there is substantial evidence for effectiveness of the drug for the secondary infection.
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Increase reliance on clinical endpoints vs. requiring microbiological culture endpoints. For example, resolution of clinical signs to normal, i.e., normothermia, return to normal hematocrit, decreased WBC, etc., may be sufficient endpoints for the immune system to control any remaining infection. Reassessment for relapse may assist in confirming that the clinical endpoint was effective
- •
Use a PCR (polymerase chain reaction) test to show that the micro-organism is no longer present in the blood.
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- 2
Expand the label to include other indications for drugs previously approved for dogs and cats:
- a)
It is assumed that if an additional indication is sought by a sponsor, essential data will already be available as des-cribed in 1.a. These data include TAS, PK, and microbiologic data. If the new indication requires a different dose, dose frequency, or duration, additional safety data should be provided to demonstrate safety for the new indication. If microbiologic data have not already been generated from the initial registration, revised microbiologic data (e.g., MIC of field isolates) should be generated, as well as evidence for the PK/PD criteria for a new indication.
- b)
If data in item 2.a. are available, an additional indication may be considered for a label if other criteria are met. These data may include:
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Abbreviated clinical trial – for example, using a smaller sample size conducted at fewer institutions – to demonstrate effectiveness.
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Data from properly conducted foreign field studies
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Animal model and PK/PD studies.
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A ‘weight-of-evidence’ approach analogous to the USP monograph process to support approval of additional indications. Publicly available or unpublished studies, when considered individually, may not support inclusion of a primary indication in product labeling. However, these data, viewed in compilation with other studies, considering strength of evidence and previously established facts about the drug and targeted infections, could be sufficient to support additional indications for a product. These reports might include species-specific evidence from randomized and controlled trials, studies of disease models, large case studies, pharmacokinetic studies with surrogate endpoints, well-designed trials in a species considered appropriate for comparison, or in vitro data. (See http://www.aavpt.org for description of USP monograph process.)
- •
- a)
- 3
Legislative/regulatory initiatives to secure innovative ways to bring antimicrobials to market and designed to help pharmaceutical companies over the financial hurdles faced in providing limited-demand animal drugs.
- a)
One approach is the development of a plan for ‘conditional approval’ of an antimicrobial. This would allow a sponsor to make a drug available before collection of all necessary effectiveness data, but after proving that the drug is safe. One model for this approach exists in the Minor Species and Minor Use Animal Health Act (2004), which provides for marketing a drug for up to 5 years, through annual renewal, while collecting additional required effectiveness data.
- b)
It may be possible to construct labeling that would reflect the type of study carried out for each indication, adjusting labeling language to reflect different levels of evidence supporting different indications.
- c)
Another recommendation is to explore the legal feasibility of broadening the scope of information allowed on labeling and FOI that would guide the practitioner in the prudent use of the product beyond the labeled indication.
- a)
- 4
Enhance collaboration among industry, academia, specialty practices, and diagnostic laboratories in the mining of data pertaining to the evidence-based, effective use of antimicrobials.
- a)
The need for collecting survey data was addressed by proposing the establishment of standardized antimicrobial susceptibility and clinical study databases. The lack of a systematic information collection process across institutions, hospitals, and diagnostic laboratories is complicated by the different laboratory standards among diagnostic facilities, and the difficulty in establishing intellectual property rights to such data.
- b)
Utilizing academic and referral institutions to conduct GCP field studies for antimicrobial drug indications that are unlikely to have microbiological cures (e.g., hemoparasites) may facilitate case enrollment and study design.
- c)
Academic and specialty experts could collaborate to develop diagnostic criteria for case reporting, and develop acceptable criteria for determining drug effectiveness for disease conditions that do not result in microbiological cures.
- a)
Conclusion
The use of antimicrobials meets an important therapeutic need for companion animals afflicted with bacterial disease. The currently limited armamentarium of antimicrobial drugs approved for a relatively small number of disease entities belies the true breadth of bacterial disease observed in companion animals. The need for additional antimicrobials with FDA-approved labeling that appropriately guides practitioner use cannot be overstated. This workshop revealed the scope and sources of some of the major challenges and provided insight on moving forward to address this critical issue in veterinary medicine. The approaches for addressing the challenges as revealed in this workshop represent the beginning of a multifaceted initiative that must involve practitioners, academic specialists, regulators, and the pharmaceutical industry. The results of these collective efforts will ultimately define the future of this key therapeutic area in small animal medicine.
