Recommendations for Designing and Implementing Protocols for Advanced Technology Clinical Trials

Introduction Products, devices, and materials for the treatment of chronic and problematic wounds have, during the course of the last two decades, progressed from simple dressings acting as protective coverings to more complex drugs and biological devices. The number of available products from which a clinician may select a treatment modality has grown from a few similar dressings to hundreds of dressings, topical ointments, creams and gels, devices, biological materials, skin substitutes, and drugs. The vast array of choices has left the majority of clinicians uncertain of product differences, benefits, and efficacy. Few well-designed studies are available to support manufacturer’s claims. Increased product cost and requests for evidence based treatment outcomes are creating a demand for well-designed, controlled, and randomized trials with appropriately powered studies to support purchase and use of treatment modalities. This is of growing importance with products claiming to interact or manipulate the wound environment. New drugs and biological devices first must meet Food and Drug Administration guidelines to determine safety and dosing followed by efficacy studies to support claims. Studies must be well designed and meet FDA requirements while providing evidence to convince the clinician that a more expensive and advanced technology is a justifiable and valid choice over less expensive and standard forms of therapy. The medical and pharmaceutical industry is confronted with the task of conducting large and expensive multicenter trials that must show superiority to justify cost or, at a minimum, to show noninferiority or equivalence of a product that is to be marketed at a lower cost than competitive products. Designing a protocol to address all the FDA, clinical, and marketing demands may be a difficult task. Clinical trials, particularly those involving biological materials and drugs, may be required to have specific inclusion and exclusion criteria that do not reflect the true medical status of the population for whom the drug or biological material may be prescribed. Study design limitations may result in an indication for a single wound etiology, yet the clinician needs to discern if and when to use the drug off-label. While pharmaceutical companies are restricted to marketing a product only for its labeled use, there is no law that prohibits a prescribing clinician from using the product in any circumstance where the clinician believes it to be of significant benefit to the patient. This places a further burden on studies to demonstrate efficacy for a specific wound etiology and wound repair in general. Currently available products as well as those undergoing clinical trials are designed to be used as adjuncts to appropriate wound care, yet studies frequently focus more on the etiology of the wound than on the repair process and understanding underlying pathophysiology. An understanding of the complexity of chronic wounds must be fostered through further education and cooperation between the FDA and the medical industry. An example of difficulties encountered in developing and introducing advanced products for chronic wounds is reflected in a currently prescribed topical growth factor. The study was limited to plantar diabetic foot ulcers on the neuropathic foot. Once completed, the indication was based on the ulcer etiology; however, growth factors are not specific for plantar diabetic foot ulcers on neuropathic feet. They may be applied on any diabetic foot ulcer that has undergone prior wound bed preparation and where the patient does not have contraindications to using the drug. There also may be benefit to nondiabetic patients with chronic wounds located at sites other than the plantar foot. Development of topical enzymatic products has also encountered barriers. Enzymes may be useful in assisting with debridement. Once a wound bed is free of necrotic and fibrotic tissue, wound closure is facilitated. Yet the FDA also may demand closure as an endpoint while not fully realizing the benefits of debridement alone. Enzyme study endpoints may require “graft ready” wounds although these wounds may never be grafted if the patient is not a surgical candidate for grafting. Wound closure may be required as a primary endpoint for enzymatic studies although enzymes may not be needed once a clean wound bed has been attained. Thus, not understanding treatment goals may prevent needed clinical trials from being initiated Current advances into gene therapy best exemplify the need for well-designed and realistic studies. Biopsies may be requested to determine viral levels, yet significant opposition may exist to taking biopsies from wounds under the misconception that biopsies in the chronic wound population, particularly people with diabetes, will not heal and may lead to greater problems. This is despite evidence that biopsy sites in the presence of adequate blood supply heal while the wounds do not. The novelty of gene therapy and the use of viral vectors require extensive and specific inclusion and exclusion criteria, thereby eliminating the majority of patients seen in the typical outpatient clinic from being enrolled in the study. Does this imply that the final product, if approved and marketed, will only be indicated or effective on a limited number of patients similar to those in the study, while excluding patients with typical medical problems? Clinical reality and good scientific method must merge in a well-designed study hoping to demonstrate significant clinical efficacy, safety, and relevance to the overall wound population to whom the treatment may be prescribed. Study considerations must also weigh the cost and outcome value to the developer of the product. A study needs to be designed to only include valuable and essential tests and costs while not sacrificing credibility and safety. The following information is meant to serve as a template and guide in developing protocols for advanced treatment modalities. It is the hope of the author that it will provide some assistance to companies confronted with the task of initiating clinical trials, insuring safety and federal guidelines are met, and developing a product that is marketable. Selecting a Study Population Study protocols are most commonly designed to study one wound etiology as this simplifies enrolling a demongraphically equivalent population. Statistical significance needs to be demonstrated for each wound etiology, frequently requiring large numbers of patients to be enrolled. The demand for separate studies for each wound etiology results in large multicenter trials, which may be cost prohibitive. Selecting the most optimal study population may be a dilemma for the study sponsor. Diabetic, pressure, and venous ulcers are primarily considered as a result of their prevalence and associated morbidities. This should not discourage the study sponsor from considering other types of wounds outside the three listed. Select dehisced surgical wounds, wounds secondary to trauma, and slow healing pilonidal cyst excision sites are examples of wounds that need to be considered. Pressure ulcers are the most difficult to study as this population is associated with the elderly, complex medical problems, and an environment that may be very difficult to control. Standardizing pressure reduction surfaces, particularly pressure relief surfaces, may make the study cost prohibitive. Attrition rate in this group dictates a higher enrollment number to attain an evaluable population. Complications secondary to concomitant medical problems may result in frequent adverse events. As pressure ulcers are common in the elderly and in long-term settings, establishing a well-controlled and demographically equal population may be an unrealistic goal. A subset of pressure ulcer patients includes those with spinal cord injuries. While this population tends to be younger with fewer associated medical problems, it is a smaller group making enrollment more difficult. Venous ulcers comprise another frequently studied population. The primary approach to wound closure and standard wound care includes appropriate compression therapy selection. All patients should ideally receive the same type and level of compression. As most compression wraps are left on for up to one week, products requiring daily or frequent application may pose challenges. Frequent compression dressing changes are an option but will add a higher cost to the study while requiring greater patient compliance in attending multiple clinic visits throughout the week. Forms of compression that may be applied daily are available but must be weighed against cost and convenience. Debridement is known to assist in removing necrotic and fibrotic tissue, which may harbor bacteria and delay healing. The wound bed in venous ulcers requires the same aggressive debridement as other wounds, particularly for more advanced products that require cell interaction or receptor site binding. As venous ulcers are rarely neuropathic, administration of an anesthetic may be required for adequate wound bed debridement. In the absence of arterial disease, significant bleeding may also occur during the debridement process, necessitating the procedure to be performed in the operating theater. Diabetic people with foot ulcers initially appear to be an ideal population for clinical trials. Debridement is facilitated by neuropathy. The wounds are easily accessible and may be covered with a variety of secondary wound dressings. However, outside of diabetes control, compliance, and addressing concomitant medical problems found in this population, the greatest challenge is offloading the foot to avoid repetitive trauma. An offloading device needs to be chosen and worn during ambulation by the study population. Monitoring compliance is an integral part of the study. Even short periods of noncompliance with repetitive trauma may result in rapid tissue breakdown, increase in ulcer size, and poor study results in both placebo and treatment groups. When choosing a treatment population, consider all wound etiologies as well as the study’s primary endpoint. Most advanced products, including growth factors, tissue replacements, and gene therapy, address cellular mechanisms in the wound environment, not the underlying pathophysiology. If product safety and efficacy can be demonstrated in patients with chronic and problematic wounds, one may expect a similar result in other etiologies, but only if concomitant problems are addressed. A single product indication does not mean that clinicians will or should restrict product use only to the approved wound etiology. However, it does mean that healthcare providers may restrict reimbursement approval based on the FDA approved indication. Product Considerations Prior to proceeding into a phase 1 or subsequent clinical trial, the sponsor must carefully review all competitive products on the market from a clinical value and cost prospective. The following considerations exist: 1. What is the scientific value of the product from an efficacy perspective? 2. What is the cost of the final product compared to competitors? Does clinical value justify the cost? 3. Is the product easy to use or administer? Are patients usually compliant with its use? If a product is noninferior, equivalent, or superior (without showing a statistically significant benefit), the product will be seriously considered as a treatment option, provided it is available at a cost substantially lower than its competitor. Statistical significance related to superior outcome is not always a necessary study endpoint. Advanced products, while offering treatment advantages, may be cost prohibitive or nonreimbursable by healthcare providers. Product cost needs to be incorporated into documentation related to pharmacoeconomics. Regardless of how superior a product may be to currently available technologies, products that are not reimbursed or are too expensive for a patient to purchase, will have limited if any success in the wound market. Materials and Methods Advanced modalities are initially tested in vitro and in animal trials. Formulation of the product may not take into consideration the final delivery system to be used in the clinical setting. Drugs, tissue replacements, and gene therapies are easily administered in animal models. Maintaining a drug or device over an artificially created wound in an artificial environment is relatively uncomplicated resulting in unforseen difficulties with clincial applications. Companies may rarely consider the myriad of problems that cannot be recreated in the wound setting. This may be exemplified by trials enrolling diabetic ulcers. Although mice with induced diabetes are available for animal trials, only the alteration in glucose levels and repair process have been reproduced in this model. While glucose levels are of concern in the control of the diabetic patient, primary factors influencing healing (e.g., repetitive trauma and loss of protective sensation) cannot be reproduced. Amount of exudate, pressure reduction or relief, and the multiple medical problems associated with the diabetic patient are absent in the animal models. Not considering all factors in designing initial trials may result in adverse events, which are not directly product related yet influence the outcome of the trial. Secondary dressing selection and adjunctive treatments are very important in the treatment of the diabetic foot. A gene therapy or growth factor may be delivered in a viscous or gel form. What happens when this is applied to a non-infected exudating wound on the plantar weight-bearing surface of an ambulatory patient and left on for extended periods of time under occlusion? While the study drug may not cause any problem, occluding and maintaining high levels of moisture may lead to extensive maceration which, when present in conjunction with inadequate pressure relief and repetitive trauma, may lead to further tissue breakdown and wound deterioration. Prolonged maintenance of chronic wound fluid over a wound surface without adequate dressing absorption or wicking on a patient with a compromised cellular immune response and a contaminated or heavily colonized but noninfected) wound, may result in a clinical infection. While the above occurrences are not related to the drug itself, they are still considered adverse effects, which must be reviewed on an individual basis and reported to the investigational review board (IRB) and FDA. The adverse events may delay study progress or even prevent a study from progressing as a result of poor study design. Weight bearing was discussed for the diabetic population. Offloading or pressure reduction needs to be standardized for all patients in the study as results will be directly affected by pressure. Data is available to help a company choose the least expensive and most effective offloading device for the study. The selection of the device should be determined at the time of the Phase 1 study and repeated through subsequent phases. Standardizing compression is equally important in venous ulcer studies. Variations in compression devices and treatments may adversely affect results. Selecting the same compression for all patients may eliminate a percentage not able to tolerate a certain device, yet will ensure standardization of treatment. Inclusion and Exclusion Criteria Inclusion and exclusion criteria will vary depending on the product or drug tested. Whatever the wound treatment may be, the study must be designed with the realization that patients with wounds do not, overall, comprise a healthy population. This is best exemplified by patients with pressure and diabetic ulcers but may exist in patients with venous and other wound etiologies. Blood chemistry and laboratory and diagnostic testing may be necessary to determine any effect on relevant organs and body systems. Tests that are irrelevant or offer little insight into the treatment are expensive and may be invasive for the patient. When establishing lab ranges, particularly with blood chemistry, consider the patient population under investigation. Lab values that are found only in healthy individuals without medical problems or wounds may not be realistic for the study population. When a treatment is finally approved, it needs to be applicable to the majority of patients in the treatment category if there is to be a clinical benefit. Clinicians are inclined to prescribe new therapies for patients with wounds that are difficult to heal rather than those responding well to standard approaches. Consents Guidelines for informed consents are available from most IRBs. Templates are routinely modified according to local review board recommendations. Of particular importance are the new confidentiality guidelines, which are available through the internet. Investigator Selection and Training Selection of an optimal study site and investigators is as critical to study outcome as selection of the appropriate patient population. Common and repeated errors are seen by sponsors determining where to initiate their trials. Each of the following considerations will affect study outcome. Investigator experience with wound etiology under consideration. A sponsor may feel that a specific medical specialty may provide the best investigators for a certain type of wound, e.g. venous. While this may be the case at select sites, these wounds may be treated on a frequent and regular basis at sites where these specialists do not participate in wound care. This is not meant to understate the importance of any particular medical specialty in the treatment of chronic wounds; rather it is to emphasize the diversity that occurs with clinicians providing wound care. Clinics and investigational sites may be under the direction of nurses, physicians assistants, or nurse practitioners, even though a medical director may oversee activity. Selecting a site where the investigating group is well experienced and knowledgeable in the treatment of the wound under consideration is of greater importance than selecting a site based on the clinicians’ specialty. It is not unreasonable to ask for a list of publications, lectures, and other materials that the investigator may have related to the wound addressed. Ask if the investigator is actively involved in wound treatment; if his or her experience is not recent, how familiar is he or she with current treatment modalities? Does the site have a dedicated research staff member? In what number of studies have they participated? Have there been problems or disagreements in staff interaction? Determining if there have been any past problems with an investigator, his or her IRB, and/or the FDA may prevent the need to invalidate a research site. Avoid potential unwanted legal complications by reviewing the medical licenses and curriculum vitae of a site’s investigators. Site selection. Considerations for an optimal site include but are not limited to an affiliation with an acute care facility, medical center or university, patient accessibility, patient numbers, availability of diagnostic equipment, and reputation. How many patients per month or year does the site see? How many are new patients? How many visits are follow-up visits? What are the percentages of different wound etiologies? Does the site have easy access to laboratories and diagnostic tools on site or must the patients go off site? If the site is a hospital, have there been any problems with accreditation? Have any lawsuits been initiated in the past due to a study? Has the FDA ever audited the site? Selecting an “ideal site” may be difficult. Consider a smaller more experienced and reputable site that does not have competitive ongoing studies over a large free standing site with large patient numbers but without any trial experience or with too many other studies being conducted. Selecting a site associated with a very recognized name but without the patient requirements may be a gross error in judgment. Sites that enroll large numbers of patients that later must be excluded or sites that enroll few to no patients are equally disadvantageous. Statistical Analyses and Study Enpoints The method of statistical analyses will be determined by the study endpoints. Unless a phase IV study is being conducted for marketing or product support purposes, a correctly powered study with an adequate number of randomized, controlled, and preferably double-blinded numbers of patients will have the greatest credibility. Randomized, phase III studies with inadequate numbers of patients are not acceptable. Large studies will incur high costs but are mandatory for the new advanced products. Information obtained from phase I and phase II trials assists in eliminating unnecessary testing, costs, and procedures. Debate is not uncommon between marketing and scientific departments of pharmaceutical and medical device companies when designing clinical trials. Establishing open lines of communication while mutually agreeing to goals may save time and money. The determination of a study’s primary and secondary endpoints will help guide a company in determining how a study is to be powered and how many patients will need to be enrolled. While complete wound closure is desired with most new products, this does not have to be the primary endpoint. Reduction of bacterial levels to reduce risk of critical tissue infection, debridement of nonviable tissue from a wound bed to promote closure, improved quality of life, decreased cost of care, as well as other concerns related to wound treatment may be acceptable endpoints. Overcoming the misunderstanding that wound closure is the most important endpoint may be a difficult task. As previously mentioned, the importance of debridement has been extensively discussed in the medical literature, yet it may not be considered an adequate primary endpoint by the FDA unless sufficient well-designed trials become available to indicate that patients randomized to a debridement versus no debridement group progress to closure at different rates. Large, multicenter, well-designed, randomized, prospective trials on debridement alone are currently not available. Safety and Efficacy Considerations for the Industry and the FDA A brief review of safety and efficacy related to advanced research modalities is warranted. Only a few of the key issues are discussed. Recurrence rates. Wound recurrence in pressure, venous, diabetic, and many other wound etiologies may be independent of the treatment choice. Recurrence in the diabetic population is directly influenced by repetitive trauma, unrelieved high levels of pressure, and localized ischemia with subsequent tissue damage. Venous ulcers have a documented high recurrence rate in the absence of continued use of appropriate levels of compression. While an advanced therapy may influence a wound’s ability to close, recurrence of venous ulcers is directly influenced by the presence or absence of post-wound closure compression therapy. The overemphasis in protocols placed on recurrence of wounds emphasizes the lack of understanding concerning underlying pathophysiology. Current drugs, biologics, and even gene therapy do not address diabetes, pathology of venous disease, or pressure reduction. Biopsies. Any biologic or drug with the potential for local tissue and systemic effects requires both systemic and local monitoring. Biopsies may be required to monitor tissue drug levels and tissue response to treatment. Gene therapy delivered through viral vectors will require systemic testing as well as local biopsies to determine persistence of the agent and the vector. This poses a dilemma as biopsies are viewed as invasive and possibly harmful in the chronic wound population, particularly diabetics. Retrospective studies on large numbers of patients who have received wound biopsies and the sequelae of biopsying are needed to substantiate the low incidence of complications associated with the biopsy alone. It would be of questionable ethics to conduct a randomized, prospective trial solely for the purpose of taking biopsies. Debridement. Aggressive wound debridement to the level of viable tissue is important in studies involving gene therapy, growth factors, and products requiring cellular interaction. There is little if any known benefit of applying the currently available and approved advanced therapies to wounds that have extensive necrotic and/or fibrotic tissue. Patients must have adequate blood flow to the wound site and not have any condition that may significantly impede healing prior to aggressive debridement. An avascular population may not be ideally suited for use of advanced products. Degree and method of debridement varies between sites and clinicians. Education and training on debridement methods for all investigators prior to a study may assist in providing more uniform and desirable results. Graft-ready wounds. A trial designed for debridement may require a wound to be graft ready or grafted as an endpoint. This represents a misunderstanding of chronic wounds as many patients are not grafted and are treated conservatively simply because they are not graft candidates. Other wounds may benefit from debridement through reduction of bacterial colonization in nonviable tissue, yet may never be graft ready. The assumption that all patients will eventually have wounds that close and that closure should always be the primary endpoint represents a misconception about patients with chronic wounds. Wound etiologies, patient medical status, and potential to heal vary significantly. This does not mean excluding the most appropriate care to patients with no ability to heal. Endpoints with the latter population may include decreased pain, increased quality of life, and preventing further wound deterioration and complications. Summary Designing, implementing, and conducting a well-designed clinical trial demands a thorough review of the product, selection of a relevant patient population, and final patient benefit. Collaboration, discussions and on-going communication between intradepartmental staff of study sponsors and between the company and the investigators is needed to ensure credible study design and outcomes. While only a general outline of considerations has been presented, details of study protocols will be specific to the device, drug, or biological material being studied. Further cooperation between the medical industry, regulatory agencies, and clinical investigation sites is needed to establish well-delineated guidelines for research with advanced treatment modalities for chronic and problematic wounds.