A Comparison of the Regulatory Requirements and Processes of the Center for Veterinary Medicine and the Veterinary Drugs Directorate as Applied to Veterinary Drugs for Use in Companion Animals

This content was archived on June 24, 2013.

November 2002

Help on accessing alternative formats, such as Portable Document Format (PDF), Microsoft Word and PowerPoint (PPT) files, can be obtained in the alternate format help section.

Table of Contents

• Goal of Veterinary Drugs Directorate
• Objectives of Contract
• Scope of Contract
• Introduction
• Methods
• Results and Discussion:
• Conclusions
• Appendix I
• Appendix II
• Appendix III

Goal of Veterinary Drugs Directorate

To assess the feasibility of harmonizing the approval of veterinary drugs for use in companion animals in the United States with Canada.

Objectives of Contract

To examine the regulatory requirements for establishing the efficacy and safety of veterinary drugs for use in companion animals¹ (dogs and cats) in Canada and the United States.

The main classes of drugs to be covered include antimicrobials, antiparasitics, anaesthetics, anti-inflammatory and endocrine² drugs.

Scope of Contract

To identify any (substantive) differences in the regulatory requirements (and review criteria) between Canada and the United States.

Introduction

The issuing of an Approval or Notice of Compliance (NOC) for a new veterinary drug for companion animals is the culmination of a process designed to ensure the safety and efficacy of the drug in the intended species (target animal) for the intended use (indication). The regulation of this process is the mandate of the Center for Veterinary Medicine (CVM) in the United States of America (USA), and the Veterinary Drugs Directorate (VDD) in Canada. In the USA, the legislative authority for the regulation of veterinary pharmaceuticals is provided by the Federal Food, Drug and Cosmetics Act. The legislative basis for the regulation of veterinary pharmaceuticals in Canada is embodied in the Canadian Food and Drug Act, specifically Part C. In both countries the regulations based on the Acts include specification of requirements for the studies conducted in the investigation of the efficacy and the safety of the drug; a review of the data submitted in support of licencing the drug for the specified uses in the intended species to ensure scientific validity of the data and the conclusions drawn; and requirements for the information on the drug, and instructions for the use of the drug, that are to be provided to the end user (veterinarian or companion animal owner) to ensure that the drug is used in a safe, effective and responsible manner.

Methods

In addressing the goal of the VDD as stated above, the author considered that there were essentially two distinct, potential approaches:

1. A comparative assessment of randomly selected drugs for companion animals, which had been approved in the USA and Canada, with respect to:
   1. Application/submission content;
      
   2. Documentation of the review process; and
      
   3. Product label/insert content,
      
   in sufficient numbers to have a high degree of confidence in the subsequent analysis of the correspondence between the regulatory process of the two countries as they affect companion animal drugs, and the basis for any differences. Or,
   
2. A comparative assessment of the requirements of the regulatory processes of the CVM³ and the VDD as revealed by published documents, and by on-site and telephone interviews of personnel of the responsible Divisions of the Agencies. Specifically:
   
   1. Application/submission requirements;
      
   2. Requirements of the studies to establish the efficacy and the target animal safety of various categories of drugs for companion animals;
      
   3. Review criteria and the review process; and
      
   4. Product label/insert content requirements.
      
   Inherent in this type of analysis is the assumption that given the same study requirements, same application/submission content, application/submission review personnel of comparable qualifications, review criteria and processes which are similar, then the outcome of the determination of the efficacy and the safety of the drug should be substantively the same. For an approach which contains an assumption of this nature, it is important to establish that procedures are in place to ensure consistently high standards with respect to meeting requirements, criteria and processes over time, and from reviewer to reviewer.

Both of these approaches have advantages and disadvantages. However, the former approach (A), while providing a potential opportunity to assess how non-scientific factors such as national policies, priorities and procedures may influence the outcome of the review of the application or submission, is a much more labour intensive undertaking. In addition, this would be very difficult, potentially impossible, to implement due to statutory constraints on the sharing of confidential or proprietary information by the Agencies of the USA and Canada.

For these reasons, the approach used to address the objectives of this contract was predominantly B, with the addition of a comparison of the review outcome of the data package of a limited number of drug products for companion animals, one drug from each of the categories specified, selected from a list provided by the VDD. The two components of the approach were:

1. A comparative assessment of the process employed in the United States and Canada to establish the delivery of safe and effective veterinary drugs for companion animals to the end users. This involved a review of:
   1. New drug application/submission requirements;
      
   2. Study requirements to establish efficacy and safety in the target species;
      
   3. Submission review criteria and process; and
      
   4. Information and instructions, provided with the drug (label and/or product insert), to the end-user.
   The list of applicable documents reviewed in this component, for a new animal drug application (NADA) to the CVM is provided in Appendix I, and those for a veterinary new drug submission (NDS) to the VDD in Appendix II. When the documents were obtained through downloading from an Internet website, the URL (universal resource locator) for the website is provided.
2. A comparative assessment of the data evaluated and the evaluation of that data which culminated in the issuing of a NOC or an approval, in Canada and the United States, for specific drugs for companion animals in each of the specified categories of anti-microbial, anti-parasitic, anaesthetic, anti-inflammatory and anti-anxiety. The specific drugs selected in each of these categories were Baytril tablets (Bayer Inc), ProHeart 6 (Fort Dodge Animal Health in the USA, Ayerst Veterinary Laboratories in Canada), PropoFlo (Abbott Laboratories), Rimadyl (Pfizer Inc) and Clomicalm (Novartis Animal Health Inc).
   
   The data available for review for the comparative assessments from the CVM were the publicly available Freedom of Information (FOI) Summaries; Where as, the VDD provided confidential submission review reports following security clearance, signing of a non-disclosure agreement with specifications by Health Canada of the security requirements for these documents, during the conduct of this contract.

Review of the documents indicated in the two components was complemented by meetings with Team Leaders and Veterinary Medical Officers of the Division of Therapeutic Drugs for Non-Food Animals during an on-site visit to the CVM in Rockville, MD, June 26-27, 2002 and by telephone interviews with the Chief and Drug Evaluators of the Clinical Evaluation Division of the VDD in late August and early September of 2002.

These meetings with CVM staff and telephone discussions with VDD staff were particularly important in the assessment of the submission review process. It was during these discussions with personnel of the Agencies that a determination was made of what procedures are in place to ensure consistently high standards with respect to the review process over time, and from reviewer to reviewer. In particular, the personnel were questioned on:

1. Standard operating procedures (SOPs) for the conduct of reviews;
   
2. Quality control procedures (QC);
   
3. Training procedures for new personnel; and
   
4. Continuing education (CE) opportunities and requirements.

Results and Discussion

Component 1

Regulation and guidance documents applicable to a NADA in the USA and a NDS in Canada

The regulations specifically applicable to the NADA in the USA are contained in the US Code of Federal Regulations (CFR), Title 21, Chapter 1, Subchapter E, Part 514 (21CFR 514). There may be other regulations in the Code of Federal Regulations which have implications for a NADA. The regulations applicable to the NDS in Canada are found in the Canada Food and Drug Regulations, Part C.

In general, the regulations applicable to, and guidance documents currently available for, new animal drug applications to the CVM are more specific, more numerous (particularly as applies to the guidance documents) and more detailed than corresponding regulation and guidance documents for new drug submissions to the VDD. Consequently the content of the CVM documents tend to be more precise and less open to interpretation. This statement applies only to the currently available documentation and is not meant to imply that one Agency is more or less rigorous or flexible in its regulations or requirements than the other.

Format and content of a NADA compared with a NDS

The Code of Federal Regulations, 21CFR 514.1, specifies the regulations applicable to the form and content of applications to the CVM, including a NADA. The formatting, assembling and submitting of a NADA is available as a draft guideline (CVM Guideline No. 41) while CVM Guideline No. 104 provides guidance to the industry on the content and format of effectiveness and target animal safety technical sections and final study reports for submission to the Division of Therapeutic Drugs for Non-Food Animals.

The Canada Food and Drug Regulations, Part C, specifically C.08.002, outlines the regulations with respect to the conditions to be met for permission to sell a new drug in Canada. Guidance on the formatting, content and submission of a NDS is provided in the document titled "Preparation of Veterinary New Drug Submissions", available from VDD.

The author of this report focussed on the regulations and requirements with respect to the content of the NADA and the NDS rather than format, assembly and submission. With respect to content, 21CFR 514.1(8)(iv) states:

"All information pertinent to an evaluation of the safety and effectiveness of the new animal drug received or otherwise obtained by the applicant from any source, including information derived from other investigations or commercial marketing (for example, outside the United States), or reports in the scientific literature, both favourable and unfavourable, involving the new animal drug that is the subject of the application and related new animal drugs shall be submitted. Include any evaluation of the safety or effectiveness of the new animal drug that has been made by the applicant's veterinary or medical department, expert committee, or consultants."

This statement has been referred to as the "total disclosure" requirement. The author was unable to identify a similar statement applicable to the content of a NDS within the Canada Food and Drug Regulations.

This difference in the stated requirement of content of a NADA and a NDS means that a NDS for a drug is very unlikely to contain information which would not be present in the NADA for this product. On the other hand the NDS content could be less than the content of the NADA for a product.

Efficacy and target animal safety study requirements

The requirements for evidence of safety and efficacy for a NADA are detailed in 21CFR 514.1(8) [Evidence to establish safety and effectiveness], 514.4 (Substantial evidence) and 514.117 (Adequate and well-controlled studies). The CVM has several published guidance documents applicable to efficacy and target animal safety studies of drugs for companion animals, including guideline numbers 33, 56, 58, 85, 90, 104, 111, and 113 (titles and URLs of these guidelines are available in Appendix I).

The requirement for safety and efficacy studies for a NDS is indicated in C.08.002 of the Canada Food and Drug Regulations. Guidance on intended species safety studies and efficacy studies for a NDS is provided in sections 3.5 and 3.6, respectively, of the document titled "Preparation of Veterinary New Drug Submissions", available from VDD.

The US CFR and the CVM guidance documents provide more precise descriptions (less open to interpretation) of the requirements and recommendations than the corresponding Canada Food and Drug Regulations and VDD guidance documents. However, in the development of scientifically sound study protocols there are no substantive differences in the factors which must be considered and incorporated in the study design and in the procedures to be used in the conduct of the studies.

The requirements of the CVM and the VDD for the design and conduct of scientifically sound, unbiased, research protocols to determine the efficacy and the safety in the intended species, of new drugs for dogs and cats, are virtually identical. Differences when they exist are differences of degree rather than differences of presence or absence of a requirement. In these instances, generally, the CVM requirements will exceed than those of the VDD. The CVM guidance documents for efficacy and target animal safety studies, irrespective of the category of drug for companion animals, contain more details and consequently may appear less flexible. However, all final versions of guidelines contain the statement:

"This guidance represents FDA's current thinking on the matter and does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative method may be used as long as it satisfies the requirements of applicable statutes and regulations."

Both Agencies encourage sponsors to discuss planned research programs and study protocol with appropriate agency personnel prior to initiating the research so that potential areas of concern may be identified and discussed.

Review criteria and the review process

The primary review criteria used in the assessment of the NADA and the NDS are the same criteria used in establishing the validity of the results of any scientific research:

1. Qualifications of research personnel;
   
2. Adequacy of study design, including appropriate controls and blinding of all research personnel to the assignment of treatments;
   
3. Absence of assumptions in the design and the study protocol;
   
4. Use of accepted, established and were possible, validated procedures;
   
5. Demonstration of documentation of observations at the time they are made;
   
6. Analysis of the results by appropriate statistical methods prior to revelation of the treatment assignment codes; and
   
7. Reproducibility of results.

In addition to these criteria for the assessment of scientific research, a paramount criterion in the review is a determination of whether the data package supports the label claim for the intended use(s) in the target species.

The Code of Federal Regulations indicates detailed requirements for the demonstration of substantial evidence (21 CFR 514.4) and for adequate and well-controlled studies (21 CFR 514.117) including in the latter specific requirements with respect to different categories of controls, and for clinical field trials. These detailed requirements place additional emphasis on these aspects as criteria of importance to the review process of the CVM.

During the assessment of the review processes of the Division of Therapeutic Drugs for Non-Food Animals, CVM and the Clinical Evaluation Division, VDD, personnel from both Agencies indicated that in addition to the criteria for scientific validity, prior NADA or NDS review reports, as well as current knowledge, policies and procedures with respect to the review of human drugs of the same category, were reviewed prior to initiating the review of a NADA or NDS. This was done to ensure consistency of the review within the Agency over time, consistency from product to product within the same drug category and between drug review agencies in the country.

Neither the CVM nor the VDD currently have SOPs in effect for the review process for NADAs or NDSs, respectively. While individual Drug Evaluators within the Clinical Evaluation Division of the VDD have evolved standard procedures for the systematic conduct of reviews, these standard procedures do not extend across all Drug Evaluators within the Division. The document published by Health Canada titled "Bureau of Veterinary Drugs - Standard Operating Procedures" while a valuable document particularly in association with "Preparation of Veterinary New Drug Submissions", is an administrative document describing the procedures of the VDD (formerly BVD). It is not a compilation of the SOPs in use in the VDD.

The Division of Therapeutic Drugs for Non-Food Animals while not currently having SOPs in effect, does have and has had for some time, manuals and check lists for each of protocol reviews and study data package reviews. The manuals are written in SOP style with pre-review instructions followed by section by section instruction, with section and sub-section headings corresponding to the sections and sub-sections of the recommended protocol and study report formats. The headings of the check list correspond to those of the respective manual. These documents go a long way towards ensuring high standards of consistency and quality of reviews within the Division. Development of SOPs for formal implementation is in progress.

Quality control of the reviewer reports of the Division of Therapeutic Drugs for Non-Food Animals is performed by the Leaders of the two Teams within the Division. (See Appendix III for a summary of the organization of the Division of Therapeutic Drugs for Non-Food Animals.) Written SOPs or manuals do not exist for the QC process, although the QC process is certainly facilitated by the protocol and study data package review manuals and check lists.

Quality control of the reviewer reports of the Clinical Evaluation Division of VDD are performed predominantly by the Chief of the Division, with an option to delegate QC if considered appropriate or desirable. The recently published document "Veterinary Drugs Directorate - Peer Review of Veterinary Drug Submissions" describes the routes by which various submissions to VDD are reviewed. As the responsibility for the QC of review reports has the potential to become more diffuse, the need for SOPs for the QC process becomes more important to ensure consistency.

It is important to indicate clearly that the recommendations for the implementation of SOPs for review and QC processes is not a criticism of the quality of current review reports. This is a recommendation which I believe would reduce the risk that a sub-standard review report could be accepted.

Training procedures for new reviewers differ between the Division of Therapeutic Drugs for Non-Food Animals and the Clinical Evaluation Division. The Division of Therapeutic Drugs for Non-Food Animals uses a combination of mentoring and one-on-one training sessions of the new reviewers by the Division's Team Leaders, as well as group training sessions on all aspects of the review process. This approach is strengthened in its consistency by the availability of the protocol and the study data package review manuals, their corresponding check lists, and QC of reviews by the Team Leader. While the Team Leaders are the main assistance resource for the reviewers, they are encouraged to discuss issues with other senior reviewers. The Clinical Evaluation Division of VDD relies primarily on a mentoring program with a new reviewer assigned to a senior Drug Evaluator within the Division for guidance, and as a resource person. The potential of this approach alone to achieve a consistent standard would appear to be somewhat less than the approach currently used by the Division of Therapeutic Drugs for Non-Food Animals. On the other hand, dependent on the mentor and the ease with which the new reviewer can and does access and interact with other senior Drug Evaluators in the Clinical Evaluation Division, this approach has the potential for the new reviewer to obtain depth and breadth of training.

From the somewhat limited information available to me, it appears that the reviewers of the Clinical Evaluation Division have a higher level of education than those of the Division of Therapeutic Drugs for Non-Food Animals. The majority of the reviewers of the Clinical Evaluation Division of the VDD have a post-graduate degree in addition to their degree in veterinary medicine. The converse is true of the Division of Therapeutic Drugs for Non-Food Animals. One should keep in mind that what was just discussed was level of formal education, not academic ability nor motivation. Fifty percent of the Veterinary Medical Officers (reviewers) of the Division of Therapeutic Drugs for Non-Food Animals, use the advantage of the flexibility of their hours at the CVM to continue to practice companion animal veterinary medicine⁴. Consequently the personnel of this Division are very current in the needs and procedures of daily veterinary medical practice. In addition, practising veterinary medicine requires them to participate in a minimum number of hours of continuing education (CE) annually.

Both the CVM and the VDD appear to offer good opportunities for CE through providing their staff opportunities to attend a minimum of one conference or training course/workshop, of the reviewer's choice, annually as well as periodic within Agency or Department training programs. It is my understanding that participation of a reviewer in CE currently is not mandatory in either the CVM or VDD.

To summarize comments on the review criteria and the review process as described above:

1. The principle criteria for the review of a NADA or a NDS are the same criteria used in establishing the validity of scientific research. However, emphasis on particular criteria in the review of the data package may be influenced by precedent, policies, procedures and priorities of the CVM or VDD or other agencies within the Food and Drug Administration or Health Canada, respectively. It is very difficult for an individual from outside the CVM and VDD to identify these factors and how they could or would influence the outcome of a NADA or NDS review.
2. The review process is more formally standardized at the Division of Therapeutic Drugs for Non-Food Animals of the CVM than in the Clinical Evaluation Division of VDD. The standardization of the review process through manuals and corresponding check-lists will have a benefit in facilitating QC standardization. Neither the Division of Therapeutic Drugs for Non-Food Animals nor the Clinical Evaluation Division has SOPs implemented for submission data package review or QC of submission review reports.
3. The qualifications of personnel of the Clinical Evaluation Division and the Division of Therapeutic Drugs for Non-Food Animals are comparable, as are opportunities for CE.
4. The training of new reviewers within the Clinical Evaluation Division and the Division of Therapeutic Drugs for Non-Food Animals are different. Each approach has its strengths and weaknesses. The procedure used by the Division of Therapeutic Drugs for Non-Food Animals would appear to ensure the more consistent standard of review but, depending on the reviewer, may not provide as much job satisfaction.

Information and instructions provided to the end user of the drug

The source of the documents used for the comparison of the information and instructions provided to the end user in the United States an Canada were two Internet websites as identified in Appendices I and II. There are risks inherent in using third-party websites as the source of this information, such as the content of the product label/insert is not the most recent version or that there may be errors of entry which could potentially be significant. The sites were used because the information format was comparable and easily readable. The identity of the first of these sites was by direct link from a veterinary medical association website.

While the headings used and the contents covered under specific headings do differ on the product label/insert for the US and Canada, the purpose is the same - to convey to the end user, in uncomplicated language, sufficient information and adequate instructions to ensure that the product can be used in a safe, effective and responsible manner. The requirements for and the formatting of product labels and inserts for veterinary drugs in Canada are specified in the Canada Food and Drug Act, Canada Food and Drug Regulations and guidance is provided by the Health Canada publication "Guide for the Labelling of Drugs for Veterinary Use". The corresponding information for the labelling of veterinary drugs in the US can be found in the Federal Food, Drug and Cosmetics Act and the Code of Federal Regulations (21 CFR 201 and 21 CFR 514).

The review and comparison of the product information and instructions to the end user for the five drugs selected for review comparisons, revealed that the correspondence ranged from virtually identical (Baytril Tablets) to sufficiently different that one could question whether the information referred to the same product or whether the content of the NADA and the NDS, on which the product label/inserts were based, were the same (ProHeart 6).

In general, from this admittedly small sample, the US product label/insert contains more information. Considering the headings of Indications, Pharmacology (including pharmacokinetics, drug interactions and adverse drug reactions (ADR) in this heading), Trial Data (summary statements of the results from efficacy and target animal safety studies) and Warnings (in Canada this applies to humans only, in the US this heading may include warnings re animals) the following statements apply to the limited number of comparisons conducted.

Indications (claim) in the US are more restrictive, and may include a descriptive qualification of the manner in which the product should be used to be effective. For example the indications for Rimadyl in Canada are "the relief of pain and inflammation in dogs" where as in the US the indications are "the relief of pain and inflammation associated with osteoarthritis in dogs". (The regulations in the US only permit a claim for those conditions for which the sponsor has provided substantive evidence of efficacy and safety.) An example of a descriptive qualifier component to an indication is apparent in the US indications for Clomicalm.

The Pharmacology component tends to be very similar with respect to the mechanism of activity (except when the state of knowledge may have changed significantly between the time of the US NADA and the Canadian NDS) and pharmacokinetics, although there were significant differences between the US and Canada information on the significance of the effects of food on the absorption of Clomicalm. Information on Drug Interactions tends to be more extensive in the US information, including extrapolation from human experience with related drugs in the information provided on Clomicalm. Information on Adverse Drug Reactions in the US product labels/inserts is inclusive where as those included in the Canada appear to be selective. This difference (if real) may reflective a philosophical difference in the criterion for deciding whether a reported adverse reaction is significant for the companion animal population at risk.

The Trial Data summary provided in the US information includes both efficacy and safety information. The Canada product label/insert may (Baytril Tablets) or may not (Clomicalm) provide this information. The product label/inserts for Rimadyl and ProHeart 6 provided Trial Data on safety but not on efficacy.

The final category of information is Warnings. As indicated above, on the Canada product label/insert Warnings only apply to humans while the US product label/insert Warnings include reference to animals. Discounting the animal component of the Warnings information of the US product label/insert, the information pertinent to humans was greater, and in the case of Clomicalm a much more serious warning than occurred on the product label/insert for Canada.

In summary, from the very limited number of comparisons conducted, the information and instruction content of the US product label/insert is greater, tends to be more restrictive and precise with respect to indications of use, and inclusive rather than selective with respect to potential adverse events.

Component 2

A comparison of the data evaluated and the outcome of the review process for selected drugs

This component of the comparison of the review process for the approval of veterinary drugs for companion animals in the United States and Canada consisted of a comparison of the reports on the research projects submitted in support of the efficacy and safety of selected drugs for companion animals. The information available to me from the CVM were the FOI Summaries for NADAs which had received approval. These FOI Summaries are public documents and are readily available to anyone with Internet access. The VDD provided me with copies of the Review Reports on the selected drugs for companion animals, following enhanced level security clearance and the signing of a Non-Disclosure Agreement with Health Canada. There was no possibility of obtaining equivalent access to review reports of the CVM. The CVM and the VDD may choose to review selected studies. Reviewing only the FOIs or the VDD's Review Reports may not reflect all studies to which the regulatory authorities had access.

It is important to emphasize that the CVM FOI Summaries and the VDD Review Reports differ considerably and serve very different purposes. First, the CVM FOI Summaries contain descriptions of only those studies which were considered by the CVM to be pivotal or corroborative in the approval of the NADA. Consequently, in those instances when a study has been reported on in the VDD Review Report but is not described in the CVM FOI for that drug, it is not possible to establish whether that study had not been received by the CVM or that it was not considered pivotal or corroborative. The VDD Review Reports are generally more detailed and descriptive than the FOI Summaries. They may also contain reviewer comments, identification of points for clarification or second opinions as well as recommendations. The VDD Review Reports generally contain considerably more information and provide more insight into the review of the data package for a particular drug.

Secondly, the CVM FOI Summaries are more consistent in format, content and quality as one would expect of a public document. The VDD Review Reports while having a generally comparable format, varied in the clarity with which the components of the Review Report were presented. Four of the five VDD Review Reports reviewed were of good to excellent quality. The fifth was of low quality and of minimal value in comparing the studies submitted in support of approval of that drug.

The comparison of the studies reviewed by the Division of Therapeutic Drugs for Non-Food Animals of the CVM and the Clinical Evaluation Division of the VDD which culminated in the NADA approval and the NDS notice of compliance have been tabulated and are presented in Appendices IV to VIII (Baytril tablets, Appendix IV; Clomicalm tablets, Appendix V; PropoFlo injectable, Appendix VI; ProHeart 6 injectable, Appendix VII; and Rimadyl caplets, Appendix VIII).

Baytril

The CVM FOI Summary for Baytril tablets (NADA 140-441) describes 11 studies demonstrating the efficacy and 17 studies demonstrating the animal safety of this drug in dogs. The VDD Review Report identifies eight and 16 studies for efficacy and safety, respectively, which are identical to those described in the CVM FOI Summary. The differences in the numbers of studies reported in support of the efficacy of Baytril tablets all involve clinical field trials. Two of the clinical field trials described in the CVM FOI Summary were not reviewed by VDD. The clinical field trial on Baytril included in the VDD Review Report was conducted by the same principal investigator involved in the third clinical field trial in support of efficacy in the CVM FOI Summary. However, the clinical field trial study reviewed by VDD had 6 rather than 7 co-investigators and involved only 80 rather than 233 client-owned dogs.

There were two differences in studies reviewed in the support of the animal safety of Baytril. First, the CVM FOI Summary describes a clinical field trial confirmation of the safety of Baytril with 16 veterinary practitioners participating, at various geographical locations in the USA, involving 270 dogs. This study was not part of the VDD Review Report. Secondly, the VDD Review Report contained a review of a pilot margin of safety study to determine joint and renal tolerance after oral administration of Baytril to puppies. This study was not described in the FOI Summary for NADA 140-441, probably because it was a pilot study.

The differences noted above are related to the timing of the approvals in Canada and the United States. Baytril tablets were registered in Canada before approval was received in the US. The two clinical trials which were not reviewed by VDD were not completed at the time Baytril was under review and subsequently registered in Canada.

Clomicalm

The CVM FOI Summary for Clomicalm tablets (NADA 141-120) presents two multi centre clinical field trial studies, one in the US, UK and France, the other in the US and Canada, demonstrating the efficacy, and five studies, including the two clinical field trials, demonstrating the safety of this drug in dogs. The VDD Review Report on this drug was of poor quality. It also describes two clinical field trials demonstrating the efficacy of the drug in the treatment of separation anxiety in dogs, neither of which corresponds in the details to the clinical field trials described in the FOI Summary. The first of the clinical field trials documented in the VDD Review Report was a preliminary study for dose determination using a pre-market formulation of the drug conducted in Belgium, France and the UK. No study details or data were presented. The second clinical field trial included in the VDD Review Report was a dose confirmation, efficacy and safety study involving multiple centres in the US, UK and France. The information in the VDD Review Report is sketchy but the data provided to VDD appears to be a subset of the data from the multi centre clinical field trial in the US, UK and France which was described in the CVM FOI Summary. The study reviewed by the Division of Therapeutic Drugs for Non-Food Animals involved two centres in the US, five centres in the UK and seven centres in France; enrolled 115 client-owned dogs, 89 of which met the criteria for inclusion in efficacy evaluation at the end of the study. The study reviewed by the Clinical Evaluation Division of the VDD involved two centres in the US, three centres in the UK and six centres in France; enrolled 84 client-owned dogs, 77 of which met the criteria for inclusion in efficacy analysis^5.

The CVM FOI Summary for Clomicalm tablets describes three laboratory safety studies and safety data analysis from the two multi centre clinical field trials for a total of five studies demonstrating the safety of the product. The VDD Review Report indicates five laboratory safety studies (one acute, four sub-acute or chronic), all of which are described in insufficient detail to summarize study design. It has been possible to identify one of these studies only as corresponding to one of the studies described in the CVM FOI Summary.

PropoFlo

The CVM FOI Summary for PropoFlo (NADA 141-098) describes two laboratory studies and multiple (9) publications from the scientific literature as sources in support of dose rationale and a large, multi centre clinical field trial demonstrating the efficacy of this injectable anaesthetic. The VDD Review Report does not contain any studies or literature reference in support of dose rationale. The CVM FOI Summary and the VDD Review Report contain the same large, multi centre clinical field trial demonstrating the efficacy of this drug.

With respect to studies demonstrating the safety of this product in dogs, the CVM FOI Summary and the VDD Review Report document the same studies. The FOI Summary also references five supportive studies from the published literature on propofol.

ProHeart 6

The CVM FOI Summary for ProHeart 6 (NADA 141-189) includes six studies demonstrating prophylactic efficacy against Dirofilaria immitis and efficacy against Ancylostoma caninum. The VDD Review Report for ProHeart 6 describes nine studies demonstrating prophylactic efficacy against D. immitis and therapeutic efficacy against hookworms. The VDD Review Report includes the description of a preliminary dose characterization study with a pre-market formulation of the drug, a dose confirmation study of the prophylactic efficacy against D. immitis, and a dose confirmation study of the therapeutic efficacy against hookworms which were not included in the CVM FOI Summary. The absence from the FOI Summary of the study conducted with the pre-market formulation is understandable. The absence of the dose confirmation study of the prophylactic efficacy against D. immitis from the FOI Summary was because it did not use the same duration of therapy as the product to be marketed.⁶

In addition to the difference in the number of studies reported as demonstrating efficacy, there was also a difference in the interpretation of the data on the efficacy of moxidectin in the treatment of naturally acquired hookworm infections. The data of this study was interpreted by the Division of Therapeutic Drugs for Non-Food Animals of the CVM as being not adequate⁷ with respect to demonstrating therapeutic efficacy of moxidectin in the treatment of Uncinaria stenocephala infections of dogs. This data was interpreted by the Clinical Evaluation Division of the VDD as supporting the therapeutic efficacy of moxidectin against U. stenocephala. This difference in interpretation combined with the additional study on the dose confirmation on the therapeutic efficacy of ProHeart 6 against hookworms resulted in the approval of for Pro Heart 6 in Canada for the claim of treatment of infections of dogs with A. caninum and U. stenocephala whereas the original ProHeart 6 NADA received approval for the claim of treatment of A. caninum infections only in the US.

The differences in the efficacy dose confirmation studies reviewed with respect to the Uncinaria stenocephala claim was due to the timing of the approvals in Canada and the United States. At the time of the approval of NADA 141-189 by the CVM, the dose confirmation study on the therapeutic efficacy of ProHeart 6 against experimental hookworm infections in dogs, by Dr. McCall was not available. At the time of the original approval of ProHeart 6 by VDD in February 2002, this study was available to support the claim of therapeutic efficacy for U. stenocephala. The CVM had access to this study as part of a supplemental application and approved the U. stenocephala indication in a supplemental approval June 13, 2002.

The CVM FOI Summary for ProHeart 6 includes six studies as demonstrating the safety of ProHeart 6 injectable whereas the VDD Review Report describes seven studies providing product safety data. This one study difference in total number is due to a difference of three studies. The VDD Review Report specifically cites two dose characterization studies (see Appendix VII) for documentation of injection site reactions as pertinent to demonstrating safety in the dog. In the CVM FOI Summary the injection site reaction information was described and highlighted in two tables in association with the efficacy results of these studies but was not re-noted under the demonstration of target animal safety. The remaining difference in the studies demonstrating the safety of the product was a repeated treatment safety study included in the CVM FOI Summary but not reviewed by the Clinical Evaluation Division of VDD.

Rimadyl

The CVM FOI Summary for Rimadyl tablets for dogs (NADA 141-053) and the VDD Review Report for the original NDS describe the same three studies demonstrating the efficacy of this non-steroidal anti-inflammatory drug.

The CVM FOI Summary presents five studies demonstrating the safety of Rimadyl, as does the VDD Review Report. Four of these studies correspond; two are different. The CVM FOI Summary describes an acute toxicity, drug tolerance study which was not reviewed by the Clinical Evaluation Division of the VDD. The VDD Review Report makes reference to a published report on the pharmacokinetics, tolerance and serum thromboxane inhibitors of carprofen which was not cited in the CVM FOI Summary.

In synopsis, there is generally little difference in the compliment of studies reviewed, for the approval of an NADA in the US or the issuing of a notice of compliance for a NDS in Canada, for drugs for companion animals. The greatest difference appears to be associated with the number of, and the details of, clinical field trials. Differences in the interpretation of data are relatively rare.

Conclusions

During the review of regulatory documents and the discussions with reviewers from the Divisions of the CVM and the VDD responsible for companion animal drugs, no substantive differences were identified between Canada and the United States in the goals of the regulatory process, the intent of the regulatory requirements or the scientific review criteria. Whether or how precedent, policy, priorities or procedures within the Food and Drug Administration or Health Canada, or other government agencies in the United States or Canada, might affect the review process of particular compounds could not be addressed in any general manner.

There are differences in the detail in which regulatory requirements are specified, being greater for the US, which renders the review process of the Division of Therapeutic Drugs for Non-Food Animals less flexible and as a consequence, potentially more consistent.

There were differences in the interpretation of data, most apparent in the importance assigned to more minor adverse drug events, such as periodic episodes of vomition or diarrhea, reported in the conduct of studies. The affect of this difference was most apparent in the information provided to the end user on the product by the label/package insert for ProHeart 6. The explanation for this difference may be as simple, and as innocent, as the difference between the significance assigned to such an event by a reviewer with the perspective of a research toxicologist (population risk assessment oriented) compared to that of a reviewer with the perspective of a small animal veterinary clinician (individual animal, "patient" oriented).

The review process of the Division of Therapeutic Drugs for Non-Food Animals of the CVM is team oriented whereas that of the Clinical Evaluation Division of the VDD to be more individualistic. There are potentially trade-offs here in the consistency and ease of implementing quality control on the review reports versus individual job satisfaction and pride of quality of work.

The scientific review process of the Division of Therapeutic Drugs for Non-Food Animals and that of the Clinical Evaluation Division are equally thorough and rigorous. The procedures in place within the Division of Therapeutic Drugs for Non-Food Animals should produce more consistent reports on which it is easier to implement quality control. To the best of my knowledge, the standards of the quality are undescribed in either of these Divisions, and are those of the Team Leaders of the Division of Therapeutic Drugs for Non-Food Animals in the CVM and ultimately of the Director of the Clinical Evaluation Division of the VDD. While, in my experience, these positions are currently occupied by highly motivated individuals with high standards of quality, it would be desirable to have the standards and procedures for QC described in an SOP. This becomes increasingly important if the responsibility for the QC of the review reports is to become more diffuse as proposed in the document "VDD - Peer Review of Veterinary Drug Submissions".

Appendix I

List of Documents Reviewed Applicable to the Division of Therapeutic Drugs for Non-food Animals, CVM

Document list for US FDA CVM

Regulatory and Guidance Documents

Designation	Title	Date	Website URL
21CFR Ch1 Part 514	US Code of Federal Regulations, Title 21, Chapter 1, Subchapter E, Part 514
	CVM Published Guidance Documents		http://www.fda.gov/cvm/guidance/published.htm
Guideline No. 2	Anthelmintics
Guideline No. 16	Freedom of Information Summary Guidelines	1985/05/10
Guideline No. 19	Animal Health Safety Criteria
Guideline No. 24	Guidelines for Drug Combinations for Use in Animals	1983/10
Guideline No. 33	Target Animal Safety Guidelines for New Animal Drugs	1989/06
Guideline No. 35	Bioequivalence Guidance	2000/10/10
Guideline No. 36	Guideline for Efficacy Evaluation of Canine/Feline Anthelmintics	1985/07/18
Guideline No. 38	Guideline for Effectiveness Evaluation of Topical/Otic Animal Drugs	1984/08
Guideline No. 41	Draft Guideline for Formatting, Assembling, and Submitting New Animal Drug Applications	1992/06
Guideline No. 56	Protocol Development Guideline for Clinical Effectiveness and TargetAnimal Safety Trials	2001/07/10
Guideline No. 58	Good Target Animal Study practices: Clinical Investigators and Monitors	1997/05
Guideline No. 82	Development of Supplemental Applications for Approved New Animal Drugs
Guideline No. 85	Good Clinical Practice; VICH GL9 Final Guidance
Guideline No. 88	How to Use E-Mail to Submit a Request for a Meeting or Teleconference to the Office of New Animal Drug Evaluation
Guideline No. 89	Environmental Impact Assessments (EIA's) for Veterinary Medicinal Products (VMP's) - Phase I; VICH GL6 Final Guidance	2001/03/07
Guideline No. 90	Effectiveness of Anthelmintics: General Recommendations; VICH GL7 Final Guidance	2001/10/11
Guideline No. 104	Content and Format of Effectiveness and Target Animal Safety Technical Sections and Final Study Reports for Submission to the Division of Therapeutic	2001/07/10
Guideline No. 106	The Use of Published Literature in Support of New Animal Drug Approval	2000/08/31
Guideline No. 108	How to Use E-Mail to Submit Information to the Center of Veterinary Medicine	2001/02/01
Guideline No. 111	Effectiveness of Anthelmintics: Specific Recommendations for Canine; VICH GL19 Draft Guidance	2000/09/26
Guideline No. 113	Effectiveness of Anthelmintics: Specific Recommendations for Feline; VICH GL20 Draft Guidance	2000/12/12

Freedom of Information Summaries

Designation	Title	Date	Website URL
NADA 140-441	Freedom of Information Summary - Baytril® Antibacterial Tablets	1988/12/27	http://www.fda.gov/cvm/FOI/1485.htm
NADA 141-189	Freedom of Information Summary - ProHeart® 6 Sustained Release	2001/06/06	http://www.fda.gov/cvm/FOI/141-189.pdf
NADA 141-053	Freedom of Information Summary - RIMADYL® Caplets	1996/10/25	http://www.fda.gov/cvm/FOI/1042.htm
NADA 141-120	Freedom of Information Summary - Clomicalm® Tablets	1998/12/10	http://www.fda.gov/cvm/FOI/141-120.pdf
NADA 141-098	Freedom of Information Summary - PropoFlo™ Intravenous Anesthetic	1998/03/13	http://www.fda.gov/cvm/FOI/891.htm

Please note, the links below are username and password protected. To access the Website URL's please use the following username and password:

Username: country
Password: msds

Also note the documents reviewed may not be the most recent version but were the most recent version available to me.

U.S.A. Product/Label Insert

Designation	Title	Date	Website URL
NADA 140-441	BAYTRIL® (enrofloxacin) Antibacterial Tablets for Dogs	2002/05/07	www.compasnac.com/cvp/10/1040/1040012.htm
NADA 141-189	PROHEART® 6 (moxidectin)-Sustained Release Injectable for Dogs	2002/05/07	www.compasnac.com/cvp/10/1003/1003269.htm
NADA 141-053	RIMADYL® (carprofen) Non-Steroidal Anti-Inflammatory Caplets for Dogs	2002/05/07	www.compasnac.com/cvp/36/3690/3690137.htm
NADA 141-120	CLOMICALM® (clomipramine hydrochloride) Antidepressant Tablets for Dogs	2002/05/07	www.compasnac.com/cvp/11/1131/1131000.htm
NADA 141-098	PROPOFLO™ (propofol) Anesthetic Injection for Intravenous use in Dogs	2002/05/07	www.compasnac.com/cvp/10/1024/1024008.htm

Appendix II

List of Documents Reviewed Applicable to the Clinical Evaluation Division, VDD

Document list for Health Canada, VDD

Guidance and Regulatory Documents

Designation	Title	Date	Website URL
CF&D Regs	Canada Food and Drug regulations, Part C
	VDD Guidance Documents
	Preparation of Veterinary New Drug Submissions	1991
	Guide for Labelling of Drugs for Veterinary Use	1992
	Bureau of Veterinary Drugs Standard Operating Procedures	1999
	VDD - Peer Review of Veterinary Drug Submissions	2002

Submission Review Reports

Designation	Title	Date	Website URL
	Baytril® Tablets (15, 50 and 150 mg)		not applicable
	ProHeart® 6 Sustained Release Injectable		not applicable
	RIMADYL® Caplets		not applicable
	Clomicalm® Tablets		not applicable
	PropoFlo™ Intravenous Anesthetic		not applicable

Please note, the links below are username and password protected. To access the Website URL's please use the following username and password:

Username: abcdef
Password: abcdef

Also note the documents reviewed may not be the most recent version but were the most recent version available to me.

Canadian Product/Label Insert

Designation	Title	Date	Website URL
DIN: 02239524	BAYTRIL® Pr (enrofloxacin) Tablets and Injectable Solution; Bayer; 15 mg tablet		www.compasnac.com/cancvp/12/1223/1223007.htm
DIN: 02239525	BAYTRIL® Pr (enrofloxacin) Tablets and Injectable Solution; Bayer; 50 mg tablet		www.compasnac.com/cancvp/12/1223/1223007.htm
DIN: 02239526	BAYTRIL® Pr (enrofloxacin) Tablets and Injectable Solution; Bayer; 50 mg tablet		www.compasnac.com/cancvp/12/1223/1223007.htm
DIN: 02245422	PROHEART™ 6 Pr (moxidectin); Ayerst		www.compasnac.com/cancvp/11/1157/1157172.htm
DIN: 02239914	RIMADYL™ Pr (carprofen) Caplets; Pfizer; 25 mg caplet		www.compasnac.com/cancvp/11/1198/1198090.htm
DIN: 02239915	RIMADYL™ Pr (carprofen) Caplets; Pfizer; 75 mg caplet		www.compasnac.com/cancvp/11/1198/1198090.htm
DIN: 02239916	RIMADYL™ Pr (carprofen) Caplets; Pfizer; 100 mg caplet		www.compasnac.com/cancvp/11/1198/1198090.htm
DIN: 02239207	CLOMICALM® Pr (clomipramine hydrochloride); Novartis; 5 mg tablet		www.compasnac.com/cancvp/12/1231/1231003.htm
DIN: 02239206	CLOMICALM® Pr (clomipramine hydrochloride); Novartis; 20 mg tablet		www.compasnac.com/cancvp/12/1231/1231003.htm
DIN: 02239205	CLOMICALM® Pr (clomipramine hydrochloride); Novartis; 80 mg tablet		www.compasnac.com/cancvp/12/1231/1231003.htm
DIN:	PROPOFLO™ Pr (propofol); Abbott(only US Product/Label Insert available on website  www.abbott.com)

Appendix III

Personnel Structure of the Division of Therapeutic Drugs for Non-food Animals

Division of Therapeutic Drugs for Non-Food Animals, CVM (Staff complement as of June 29^th, 2002)

Director 1

Application Examiner 1
Pharmacologist 1
Consumer safety officer (contractor) 1

Team 1: Companion Animals and Wildlife Drugs

Leader 1
Veterinary Medical Officers 5

Team 2: Equine and Antimicrobial Drugs

Leader 1
Veterinary Medical Officers 6
Consumer Safety Officer 1

Total staff 18