Variables affecting clinical evaluation approval of new wound sealant/closure products

In general terms, the process of clinically evaluating new medical approaches proceeds through several phases from off-label usage to “General Approval” and then on to approval of many incremental product adaptations. Initially, physicians often begin to use technologies from other industries in improvisation mode (“off-label”) because approved alternatives do not exist. An example of this is the off-label use in the United States throughout the 1980s and early 1990s of fibrin sealants imported individually by surgeons for use in their own practices. For instance, surgeons might clip pieces of a solid sealant, mix these with saline and use the off-label mixture as a way to prevent adhesions.

Often the next stage is the clinical development of new technologies for specific critical diseases for which there is no alternative. An example is the approval of fibrin sealant in the United States for use on neonates during surgery. Another example is the orphan approval for use of cyanoacrylate adhesive for specific neurological avascular necroses.

One way that regulatory authorities may limit the early use of products is to restrict insurance claims to those precise indications shown in clinical trials to have benefit. Companies are only allowed to promote and describe the use of products for these indications. Slowly, these fields of use, and claims, are broadened through extensive clinical trials and gradual reporting of off-label clinical use in peer-reviewed articles. General approval usually follows considerable volume use of the product and the passing of a number of years of safe use without Medical Device Reports (MDR). Companies may eventually apply for approval to market the product for additional indications.

Sutures and staples have been around for many years, and are at a mature stage in the product life cycle. The materials are well established and cover most of the spectrum of clinical need for suturing. However, a great number of procedure-enhancing devices have been developed in the last several years, particularly as minimally invasive surgery and robotics have created a need for new instrumentation to secure tissue. Good examples of this are the development of stapling devices for pneumostasis and securement devices for arthroscopy.

Commercial forms of pooled human fibrin have been used clinically outside of the United States for many years, for reasons of preventing infection; however these products did not reach this stage of clinical evaluation in the United States for many years. In 1996, the FDA approved the clinical investigation of fibrin sealants and a number of trials commenced. These resulted in a cascade of approvals for specific indications and claims, and considerable off-label use and clinical evaluation. Fibrin sealants have been employed and reported to prevent bleeding in many types of procedures including cardiovascular (e.g., restiotomy), neurological (e.g., craniotomy), orthopedic (e.g., knee replacement), spinal (e.g., vertebral fusion), cosmetic (e.g., breast augmentation) and digestive (e.g., closure of temporary colostomy).

Alternatives to fibrin sealant have been developed and launched with specific claims and targeting precise indications. Cyanoacrylates have been employed as external suture replacements since 1997 in the United States. These materials started life as off-label sports injury products; they were approved with limited claims, which were then expanded to include “reduced injection risk,” and general use of these products for topical application is well established; reports from major suppliers suggest that at least 30% of the accident and emergency opportunity for treating lacerations in the United States is penetrated by cyanoacrylate glue products.

Variables Associated With Clinical Evaluation of Closure and Securement and Related Products 

VariableRapid EvaluationDelayed Evaluation
ExpenseLow cost if short follow-up, (e.g., cuts and grazes) and low-cost procedureHigh cost if long-term follow-up required, (e.g., ligament repair) and high cost procedure
Follow-up periodSome procedures require short follow-up periods (e.g., hemostasis endpoints and use of cyanoacrylate on cuts)Some procedures require at least two years follow-up (e.g., musculoskeletal sports injuries)
Surgical settingCommunity care (lacerations)Theater (surgery)
Doctor's surgery (accidents)Critical care (e.g., burns)
TechnologySome devices and developments have predicate devices which allow more rapid approval. Autologous products are also relatively quick to developNew biologicals, complex mixtures of biomaterials, and new chemical entities require extensive validation and testing
Device for deliveryCan accelerate clinical approval and improve clinical efficacyCan complicate clinical development if both device and product are new

Source: MedMarket Diligence, LLC; Report #S190.