Surgical Adhesives & Sealants

urrent Technology and Applications

David H. Sierra

• Publisher: CRC Press
• Year: 2020
• ISBN:
  9781000673210
• Edition: 1
• Topic: Medicine
• Subtopic: Ethics in Medicine

Surgical tissue adhesives are an ancient idea, going back to the beginnings of recorded history. The concept of adhering, rather than suturing, packing, or stapling planes of tissue is attractive, in that it is fast-acting and assures complete closure. Numerous technologies have been tried; some with limited success, others outright failures. In short, the perfect adhesive does not exist. Limitations occur in a number of areas: strength, toxicity, degradation, and safety. It is also important to keep in mind that "one size fits all" does not apply to adhesives in surgical applications any more than it does in day-to-day application. As one would not use paper glue to seal a bathtub, one would presumably not apply an adhesive onto tendons, which is suitable for sealing corneas. The properties required of an adhesive for each indication are quite different.

Over the last twenty-five years, advances have been made in a wide range of technologies targeting some embodiment of a practical and safe adhesive. Foremost and successful among these are cyanoacrylates, marine adhesive proteins, and fibrin-based sealants. Another promising adhesive technology is laser solders, a mixture of polypeptides and proteoglycans, which integrates with the repair site when laser energy is applied.

In light of these advances in the field, the Symposium for Surgical Tissue Adhesives was organized and held at the Atlanta Hyatt from October 8-10, 1993. The goal was to bring together these far-flung technologies in a comprehensive and cohesive manner. Presentations by investigators from around the world described the history of adhesives in medicine, current technologies, laboratory characterizations, and application developments, as well as regulatory aspects and clinical applications. We felt that as many viewpoints as possible, however conflicting, were important to present in order to give the most complete picture of the state of the art of surgical adhesives.

SECTION IV

CLINICAL APPLICATIONS AND INVESTIGATIONS

Chapter 17: Fibrin Sealant and the U.S. Food and Drug Administration Review Process

W. A. FRICKE

INTRODUCTION

The United States Food and Drug Administration (FDA) is responsible for assuring the safety and efficacy of all drugs and biologics sold in the United States. The regulatory authority for drugs is contained in the Federal Food, Drug, and Cosmetic (FD&C) Act, and for biologics in the Public Health Service (PHS) Act. The FD&C Act defines drugs as “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals … and intended to affect the structure or any function of the body of man …” [1]. The PHS Act defines a biologic as “… any virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product… applicable to the prevention, treatment, or cure of diseases or injuries of man …” [2]. Although there are similarities between the definitions of drugs and of biologics, there are important differences between them.

The most fundamental of these is that a drug is typically a chemical entity that can be well-characterized with respect to its physical attributes, including its structure. A biologic, on the other hand, is typically a complex mixture of components that cannot be successfully separated and characterized. The inability to fully characterize the final product has required the regulation of biologics to rely more heavily on in-process testing and validation of production to assure product safety, potency, and consistency rather than on final product testing.

The process of licensure of biologics is similar to that for drug approval. In both cases an investigational new drug application (IND) must be filed, clinical trials performed, and an application for licensure or approval submitted to the FDA. In the case of biologics, the application for licensure is a product license application (PLA), whereas drugs require the submission of a new drug application (NDA). In addition, biologics require that the manufacturing establishment also be licensed through the submission of an establishment license application (ELA) (preparation and review of ELAs will not be discussed here). For both drugs and biologics, the safety, purity, potency, and efficacy of the product must be established. The following review will focus on the licensing process for biologics with emphasis on the design and execution of clinical trials. Issues that are relevant to clinical trials of fibrin sealant will be discussed.

INVESTIGATIONAL NEW DRUGS

All unlicensed and licensed drugs being tested for a new indication are considered investigational and cannot be marketed in interstate commerce. A sponsor wishing to perform a clinical trial on a new drug that will involve shipping the drug across state lines must submit a “Notice of Claimed Investigational Exemption for a New Drug,” commonly known as an IND. The sponsor may begin the study thirty days from the date of the submission, providing the FDA does not place the IND on “hold.” This is usually done only when there are significant questions regarding the safety of the drug or the soundness of the proposed clinical trial.

Primary concerns during the review of the IND are that adequate data have been provided to establish that a new drug is safe to use in clinical trials, and that the clinical trial to be performed will generate useful and acceptable data [3]. To accomplish these goals, the IND should include a description of the preparation of the drug and of all preclinical testing or other use of the drug (Table 17.1). The IND should describe the chemistry, manufacturing, and control procedures involved in making the drug. The drug should be characterized with respect to its physical properties, and the final container material should be described, including all excipients. Finally, the proposed clinical use and an outline of the clinical trials intended to demonstrate the drug’s efficacy and safety should be included.

Table 17.1. IND content and format.

Cover Sheet: Identify sponsor, IRB Statement, general administration

Introductory Statement: Name of drug, mechanism of action, marketing history, brief description of clinical trial.

Investigator’s Brochure: Summary of safety and clinical data.

Protocols: Plan for clinical investigation.

Chemistry, Manufacturing, and Controls: Describes the composition, method of manufacture, and quality control measures.

Pharmacology and Toxicology: Describes the studies and results upon which the sponsor has determined it is reasonably safe to conduct the clinical trials.

Previous Human Experience: Summary of other use.

Additional Information: Dependence/abuse potential, radioactive drug information.

The description of the preparation of the drug is particularly important in biologics because of the general inability to precisely characterize these types of products. For a plasma-derived product, the collection, storage, and fractionation of the plasma should be described. This includes the specific conditions under which this is done, the chemicals used in processing, and occasionally, some of the equipment used. The reviewer of a well-written IND should be able to determine aspects of manufacturing, such as temperature, pH, processing time, chemicals added, and filters and chromatography columns used. The product testing and specifications for in-process material at each step of manufacturing and on the final product should also be described.

An IND for a recombinant protein must include a description of the cloning of the gene, construction of the plasmid, the cell in which the protein is produced, the culture conditions, the purification process, and product testing. A successful IND will provide adequate biochemical and molecular biologic evidence of safety.

Toxicologic studies are usually performed on new products before the IND is submitted. These studies typically involve several different animal species that receive large doses of the product. Adverse effects may be looked for through laboratory tests, clinical observations, or pathologic examination. These studies can be valuable in detecting toxicity of a new drug and in estimating the appropriate human dose. However, species differences may complicate the interpretation of the data generated. One species may react to a drug that other species, including humans, may not react to. None of the species tested may react to a drug that has significant toxicity for humans. Interpretation of toxicity test results can also be complicated by the fact that the doses used are usually much higher than those that would ever be used in humans; thus the relevance of adverse reactions in the animals to toxicity in humans is often unclear.

A description of the proposed clinical trials should also be submitted. Typically, clinical trials are divided into three phases [4]. Phase 1 is primarily intended to assess the safety and pharmacokinetics of the drug. These trials may be done on normal volunteers or on the patient population to be studied. Data from the phase 1 trial may be used to design a phase 2 study intended primarily to demonstrate the efficacy of the drug on a designated patient population. Efficacy and safety are the primary objectives of a phase 2 study. In some situations a phase 2 trial may be the “pivotal” trial used to support licensure.

Phase 3 trials are typically larger than phase 2 and are intended to generate additional efficacy and safety data. These data are used to supplement the data gathered in phase 2 and provide an adequate basis for labeling. In some instances, a phase 4 trial may be performed. Phase 4 trials are done after the licensure of a drug and are intended to provide additional data or to answer any remaining questions regarding use of the drug. This may be related to adverse reactions or use in a particular patient group.

Many INDs include a fairly detailed plan for a phase 1 trial but, as would be expected, include only a general outline for phases 2 and 3. Following completion of phase 1, a more specific plan for phase 2 is submitted. Often this is done following a meeting with the FDA in which the details of the proposed trial are discussed. These may ...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Dedication
• Table of Contents
• Preface
• Contributing Authors
• Section I–Adhesive Technologies
• Section II–Laboratory Evaluation
• Section III–Laboratory Applications
• Section IV–Clinical Applications and Investigations
• Index