Dental, Oral And Craniofacial Technology Forum: Clinical Trial Design and Implementation

National Institute of Dental and Craniofacial Research Food and Drug Administration

MEETING REPORT

Meeting held at

LISTER HILL AUDITORIUM
NATIONAL INSTITUTES OF HEALTH
BETHESDA, MARYLAND
DECEMBER 11-13, 2001

Executive Summary

As new discoveries emerge from the laboratory, clinical trials are crucial to develop these discoveries into the next generation of products.  Successful clinical trials require effective collaboration between the National Institute of Dental and Craniofacial Research (NIDCR), the Food and Drug Administration (FDA), academia, and industry.  To promote this interaction, NIDCR and the FDA hosted the second Dental, Oral and Craniofacial Technology Forum, December 11-13, 2001 on the NIH campus.  The forum was attended by more than 60 people, including representatives from Federal agencies, industry, professional and scientific societies, advocacy groups, and educational associations and institutions.  Forum topics addressed clinical design and implementation with emphasis on NIH/FDA policies, biostatistics, funding, and stakeholder considerations.

Following opening remarks by Dr. Lawrence A. Tabak, NIDCR Director, and Dr. David W. Feigal, Jr., Director of FDA's Center for Devices and Radiological Health, Dr. Franklin G. Miller, Department of Clinical Bioethics, National Institute on Mental Health, delivered the keynote address.  Dr. Miller spoke about "The Ethics of Randomized Clinical Trials," focusing on the importance of informed consent.   He described a clinical trial case that determined the prophylactic efficacy of acupuncture in prevention of post-operative vomiting, comparing the anti-emetic effect of acupuncture with that of Ondansetron and a placebo. He recommended that ethically problematic issues should be discussed in articles publishing study results. 

As an introduction to issues related to clinical trials, five panelists, Drs. Linda Niessen, Jorgen Slots, George Taylor, Thomas Van Dyke, and Alex White, discussed various aspects. Dr. Jorgen Slots, of the University of Southern California, spoke on "Study Design and Microbiology" and compared the tests for effectiveness in placebo-controlled and active-control trials. Dr. George Taylor, of the University of Michigan, discussed "Interventions in oral health to produce changes in systemic outcomes: Considerations in planning," explaining that recent evidence suggests the possibility of a causal relationship between oral health and some acute events (such as myocardial infarctions) and chronic diseases (diabetes and coronary diseases, for example). Dr. Thomas Van Dyke of Boston University Goldman School of Dental Medicine, discussed "Phase III trials: An investigator's perspective," in which he detailed his experiences as an investigator for a large pharmaceutical company working toward approval of a new product by the FDA. Dr. Linda Niessen, of DENTSPLY, International, spoke on "Perspectives on the Research and Development Process," offering the industry perspective, the origins of new ideas, research and development, inventors, and companies interested in licensing technology.  Finally, Dr. Alex White, of Kaiser Permanente, discussed "Complementary and Alternative Medicine Approaches to Craniofacial Disorders," in which he noted that complementary and alternative medicine (CAM) is a growing part of the healthcare landscape. 

Several outcomes related to clinical trials emerged.  In the regulatory domain, the complexity involved in obtaining FDA approval of technologies that are both devices and drugs was initially seen as a problem.  In the economic area, the magnitude of the costs of clinical trials was a major theme.  Finally, the presentations emphasized that successful clinical trials are critical to launch new products and that NIDCR should explore novel mechanisms to partner with industry to encourage industry investment in development of new clinical products. 

Following the panel discussion, a unique interactive case study format session was held. Each participant was assigned to a breakout team for study of a case to identify critical issues that need to be considered in clinical trial design and implementation.  Among the topics discussed were issues related to off-label use; surrogate end points, and drug/device combination products.  Other topics included ethical issues when using human subjects, special statistical problems in dental clinical trials, and financial considerations in clinical trials.

Background

In 1998, a Memorandum of Understanding (MOU) was executed between the NIDCR and the FDA.  This unique document served as a strategic plan for a number of cooperative efforts between the two organizations to facilitate interactions between the NIDCR and the FDA regarding improvements in the quality and relevance of pre-clinical and clinical research which is directed to the development of products for use in oral health care. The principal goal of this agreement, to reduce the time between the research and development phase of a product's life cycle and its commercial availability, was to be achieved by: (1) facilitating the development and market introduction of newly-emerging, safe and effective health care products to enable oral health professionals and auxiliaries to provide higher quality services and equip consumers with the tools necessary to improve and sustain their own oral, dental and craniofacial health; and (2) providing complementary support and expertise to enable each agency to better fulfill its public health mission. It was expected that enhancing the quality of product-related research could attain this goal and thus facilitate and improve pre-market evaluations. This agreement also set forth certain working arrangements between both parties that would enable each to fulfill its respective mission more efficiently and effectively.   One such activity was the development of a "Dental, Oral, and Craniofacial  (DOC) Forum" in which NIDCR and FDA would interact with leading representatives of the regulated industry, academia, the research community, and others on issues relating to technology development and transfer, regulatory processes for acquiring market clearance, product utilization, and treatment outcomes.

The First Forum

More than 110 people attended the First Dental Oral and Craniofacial (DOC) Technology Forum that was held November 3-5, 1999 on the NIH campus.  Participants included representatives from Federal agencies, industry, professional and scientific societies, advocacy groups, and educational associations.  The Forum featured an interactive case study format in which the attendees served on teams for study of eight cases. This format helped highlight and clarify issues that need to be considered and solved to successfully bring a new technology to the marketplace.  Several outcomes related to regulatory, economic, and scientific areas emerged.  In the regulatory domain, the availability of detailed information on a new FDA web site and the emphasis on early "informal" contact with FDA were uniformly welcomed and supported.  In addition, all teams emphasized the need for new well-defined guidelines for products that may require multi-FDA center reviews.  In the economic area, several teams reiterated the need to evaluate market potential, production costs and competitive advantage prior to initiating an expensive development process.  Furthermore, marketing strategies, and if applicable, reimbursement potential need to be considered during early stage development.  In the scientific realm, the integration of engineering and computer technology as a major force in the development of medical diagnostics and therapeutics was noted in several presentations.  Overall, the presentations emphasized that the successful development and launch of a new product is optimal when individuals with research and development, regulatory, management, marketing, clinical, and educational experience join together to support the effort.  A detailed summary of the Forum was prepared as a CD-Rom disk and distributed to all participants and is available from NIDCR’s Office of Communications and Health Education.

The Second Forum

On renewal of the MOU in 2001, both organizations noted that, as new discoveries emerge from the laboratory, clinical trials are crucial to develop these discoveries into the next generation of products.  Successful clinical trials require effective collaboration between the NIDCR, the FDA, academia, and industry.  To promote this interaction, NIDCR and the FDA hosted the second Dental, Oral and Craniofacial Technology Forum on December 11-13, 2001 on the NIH campus.  The forum was attended by more than 60 people, including representatives from Federal agencies, industry, professional and scientific societies, advocacy groups, and educational associations and institutions.  The Forum’s Program and Participants are listed in Appendix 1 and Appendix 2, respectively.

Themes

The primary themes for the Forum included:

• Exploring consequences of NIH/FDA policies on research with human subjects
• Exploring the definition and interpretation of "substantially equivalent"
• Examining the criteria for the design of clinical trials for combinatorial and off-label products
• Exploring issues affecting several aspects of clinical trial design
• Developing a strategic alliance for several small companies to jointly develop and bring a new product to the dental market
• Exploring considerations, from the perspective of various stakeholders, associated with the rapid development and marketing of a new dental therapeutic agent
• Considering clinical design implications of oral products with potential systemic influences

The Speakers

Dr. Lawrence A. Tabak, NIDCR Director provided opening remarks. He noted that the Institute’s mission is to improve oral health and stressed the importance of ensuring that the quality and relevance of research at NIDCR remain at the highest possible levels.  He pointed to the Memorandum of Understanding between the FDA and NIDCR that acted to encourage and guide interactions between the two agencies.  Finally, he noted that the purpose of the Forum was to identify operational inefficiencies acting as barriers to development of new technologies and therapeutics.

Dr. David W. Feigal, Jr., Director of FDA's Center for Devices and Radiological Health (CDRH) was the next speaker.  He began by pointing out the challenges of the new millennium and noted some examples of how new devices are changing medicine.  He stressed the importance of nanotechnology in microsurgery and robotic / remote surgery.  Dr. Feigal then gave a brief history of the evolution of consumer protection.  He pointed to patent medicines in the early 1900's as one cause for the creation of consumer protection organizations, such as the FDA, and then tracked development through Thalidomide, and the Tuskegee study, where no treatment was given for syphilis, nor was informed consent sought.  Dr. Feigal also noted some high-profile examples of research fraud.  He described the FDA's processes for risk management from first human use through market approval, integrity assurance, and enforcement.  Dr. Feigal explained that the final part of the FDA's operating method was that they make science- and evidence-based regulatory decisions.

He gave a short history of the changes in evidence standards since 1904, including the removal of 10,000 products in 1962, when product effectiveness was required prior to market approval.  This was followed with some background on the wording for drug and device development standards, such as "substantial evidence" for drug approval and "valid scientific evidence" for device approval.  Dr. Feigal spoke to the evidence standard of safety and how risk/benefit calculations figure in deliberations on safety.  He explained that the definition of effectiveness is "clinically significant results."  He then outlined some aspects of "Clinical Trial Machinery."  These include outcome measurements, controls, variance reduction, number of observations, and credibility, using ethical trial practices and "bad luck prevention." Dr. Feigal closed his presentation by stressing the mission of CDRH as promoting and protecting the health of the public by ensuring the safety and effectiveness of medical devices, and pointing out that all sides have a responsibility toward that end.

Dr. Feigal addressed several questions from the audience. He was asked what is the definition of a device and who writes this definition.   He responded that all medical products are drugs, including devices.  Devices are products that do not work through chemical action, nor are dependent upon being metabolized.  He pointed to heparin as a drug that can also be used as a device.  In response to a question about how the Code of Federal Regulations is written, and by whom, Dr. Feigal explained the process called "notice and comment rulemaking" is described in the Administrative Procedures Act.

Another question centered on the follow-up on implanted devices. Dr. Feigal stated that FDA can legally require follow-up data from companies in the post-market phase for devices, but noted the difficulties inherent in such efforts.  He cited recent problems in hip replacements, which manifested long after implantation, as showing the need for long-term follow-up.

Keynote Address

Dr. Franklin G. Miller, Department of Clinical Bioethics, National Institute on Mental Health, delivered the keynote address.  Dr. Miller spoke about "The Ethics of Randomized Clinical Trials," focusing on the importance of informed consent. 

He began with a general framework of the seven ethical requirements for randomized controlled trials (RCT), based on existing ethical codes such as the Nuremberg Code and the Declaration of Helsinki.

Dr. Miller described a case, Acupuncture versus Ondansetron in the prevention of post-operative vomiting: A study of children undergoing dental surgery (Anesthesia, 2001).  The trial involved 90 children, aged 4-12 years, receiving dental restoration under general anesthesia.  The study aimed to determine the prophylactic efficacy of acupuncture in prevention of post-operative vomiting by comparing the anti-emetic effect of acupuncture with that of Ondansetron and a placebo.  The three arms of the study used intravenous Ondansetron, acupuncture, and intravenous saline as a placebo control.  The primary outcome was the number of vomiting episodes on the day of surgery.  He stated that placebo-controlled trials raise the ethical question of randomizing patient volunteers to placebo when proven and effective treatments for a condition exist.  Dr. Miller then discussed the study in reference to the application of seven criteria, including scientific value, scientific validity, fair subject selection, favorable risk-benefit ratio, independent review, informed consent and respect for enrolled subjects.  Dr. Miller also noted that the article provided no rationale for placebo use and recommended that ethically problematic issues should be discussed in articles publishing study results. 

Dr. Miller responded to several questions from the audience.  He was asked if a less expensive and less effective drug could be ethically tested against a more expensive and more effective drug and against saline.  Dr. Miller replied that it could, provided that the test was truly necessary to answer an important question and dependent upon the risks posed by placebo treatment over the course of the study.  In response to a comment that Federal regulations require inclusion of children, pregnant women, and minority groups in studies, Dr. Miller acknowledged that there was tension between the need to expand access to clinical trials for inadequately studied populations while avoiding unnecessary targeting of vulnerable groups. He also was asked if there has been any initiative to disseminate ethical guidelines for RCTs to poor countries' health authorities.  Dr. Miller replied that their international standards are being developed, but that the policy is still evolving.

Introduction to Issues Related to Clinical Trials: A Panel Presentation

Five panelists, Drs. Linda Niessen, Jorgen Slots, George Taylor, Thomas Van Dyke, and Alex White, discussed various aspects of clinical trials. 

Dr. Jorgen Slots, of the University of Southern California, spoke on "Study design and Microbiology."  Dr. Slots compared the tests for effectiveness in placebo-controlled and active-control trials.  He stated that placebo-controlled trials attempt to demonstrate superiority to a controlled treatment while active-control trials attempt to demonstrate equivalence to existing therapies. 

Dr. Slots noted that the use of an untreated control study group poses a problem for dentistry, since irreversible damage may take place before the observation period has ended.  Therefore, periodontal studies usually begin with standard therapy, followed by the therapy to be tested against placebo.  He explained that assay sensitivity could be affected by inclusion of inappropriate patients, variances in response to therapy, insufficient adherence to therapy, and concomitant medications.

Placebo-controlled trials provide strong evidence of effectiveness, but may be of limited clinical interest, since few would actually use saline placebo in treatment.  This problem leads to the "Add-On" study design, the common protocol design in periodontal disease research.  In this case, scaling and root planning are performed at baseline, and then new agents and placebo are added.  Dr. Slots explained that an "Early Escape" study design is often used, where patients are randomly assigned to receive new therapy or placebo, but a well-defined treatment failure endpoint is used for changing therapy.

In active-control trials, it must be assumed that the active control has an effect.  This type of study is often used as a non-inferiority test.  Some studies include three arms in order to assess assay sensitivity, measure the effect of a new drug, and compare active treatments.  There is a need, Dr. Slots noted, for new therapies that are not inferior to existing therapies.  Economic and competition considerations, differences in preferences and toxicities among patients, and drug-to-drug interactions all argue for non-inferior treatments to be made available.  Problems for active control trials include the fact that assay sensitivity can be small, and sample sizes need to be much larger for equivalence studies than for superiority studies.

Dr. Slots reviewed guidelines for evaluation of a study including its aim, design, and conduct, the statistical considerations, and presentation of results for efficacy and safety.  He then concentrated on study design.  He contrasted parallel, crossover, and split-mouth designs of study, and discussed some of their strengths and weaknesses. Dr. Slots also said that microbiological testing should be used to identify major periodontal pathogens, putative periodontal pathogens, and opportunistic microorganisms.

Dr. George Taylor, of the University of Michigan, discussed "Interventions in oral health to produce changes in systemic outcomes: Considerations in planning."  Dr. Taylor explained that recent evidence suggests the possibility of a causal relationship between oral health and some acute events, such as myocardial infarctions and such chronic diseases as diabetes and coronary diseases.  As a result, oral health interventions might be useful in addressing such conditions.

Dr. Taylor focused on identifying potential participant populations to determine the feasibility of a study.  He noted that beyond the primary sources of hospital and HMO populations for a potential study, backup sources such as community and support groups should also be considered.  Accessing data about potential participants, he believes, is an important task.  Relying on preexisting information has its own advantages and pitfalls, such as possibility for errors.  Dr. Taylor pointed to the advantages of using a telephone survey, such as efficiency in determining certain types of inclusion or exclusion criteria and the ability to verify contact information.  Dr. Taylor emphasized the importance of finding the proper telephone survey resource.  The organization should have healthcare survey experience, he noted, as well as recommendations from former clients.  It is important to speak to the prospective project manager, as well as to senior management.  The interviewer pool should be examined for issues such as quality and stability.  Active participation in interviewer training is critical, as well as opportunities to monitor randomly selected interviews. 

After initial contacts, recruitment, and enrollment, it is important to determine and assess primary outcomes, and to plan oral health-related outcomes.  Clinical and radiographic measures must be planned for, as well as serious consideration of host response and bacteriologic measures.

Dr. Thomas Van Dyke of Boston University Goldman School of Dental Medicine, discussed "Phase III trials: An investigator's perspective."  Dr. Van Dyke detailed his experiences as an investigator for a large pharmaceutical company working toward approval of a new product by the FDA.  Clinical trials had been completed through phase II.  In 1996, a new company was created to develop an oral product from the existing patent.  The FDA concluded that the phase II data was sufficient to proceed to phase III clinical trials.  FDA staff recommended changes in the protocol, which were implemented by the company.  Primary endpoints for the trial and indications for use were agreed upon, and extensive statistical discussions occurred.  In August 1998, two multi-center, single-blind phase III trials began.  A third, open-label trial was started to conform to International Conference on Harmonization (ICH) guidelines.  That study provided safety and efficacy data, as well as a population sufficient to adhere to safety requirements.  Dr. Van Dyke stressed the expense of the trials, which amounted to over $16 million.

In mid-1999, there was a pre-NDA meeting between the company and the FDA.  The purpose was to define analysis parameters for the trial, and included discussions of labeling.  Dr. Van Dyke noted that the FDA was helpful, assuming a "big brother" role.  He stressed the importance of open contact with regulators throughout the process to avoid surprises in later stages.  In November 1999, phase III trials were completed, and the company filed its NDA in February of 2000.  The next year was spent on the FDA review process, with FDA asking questions and the company responding.

Dr. Van Dyke detailed the exhaustive attention of an FDA audit.  He explained that, throughout the trials, the company had performed its own audits of the contract research organization.  This process resulted in an easier task for the investigators at the end of the trial, since they already knew what to expect.   In February 2001, the NDA was approved, and the company submitted advertising copy for approval.  Dr. Van Dyke described the entire process as being very smooth, and strongly recommended keeping regulators informed throughout the process.

Dr. Linda Niessen, of DENTSPLY, International, spoke on "Perspectives on the Research and Development Process".  From the industry perspective, the origins of new ideas are research and development, inventors, and companies interested in licensing technology.  Prior to clinical trial design, companies ask some basic questions: Does the product meet a need in the marketplace?  Does it facilitate delivery?  What does the product replace?  And finally, is it patented? 

Next come questions for the business plan; questions on production cost, price, market size, competitors, and return on investment.  The research and development process entails internal and external testing, clinical trials, end-user field-testing, product launch, and post-market surveillance. 

Clinical trial design also holds questions for industry, and Dr. Niessen underlined Dr. Van Dyke's earlier recommendation of strong contact with the FDA from the outset.  Is the product a drug, a device, or a biologic?  Is the product a 510K or an NDA?  Will the study be funded through a university or a contract research organization?  Other issues are also raised by clinical trials, such as the shrinking pool of experienced investigators.  Dr. Niessen looked at characteristics of end-users in technology transfer issues, and how different categories of people accept new technologies.

Dr. Alex White, of Kaiser Permanente, discussed "Complementary and Alternative Medicine Approaches to Craniofacial Disorders."  Dr. White noted that complementary and alternative medicine (CAM) is a growing part of the healthcare landscape.  Allopathic medicine causes a second condition that is incompatible or inimical to the condition being treated.  He defined complementary medicine as used in conjunction with allopathic medicine.  Alternative medicine is used in place of allopathic medicine.  Integrative medicine entails a degree of coordination between traditional doctors and alternative practitioners.

Dr. White showed a model of disease treatment that examined a specific disease model with a health promotion and hygiene approach to intervene, and an allopathic remedy once the condition reached the diagnostic threshold.  There is also a systems model, which looks at spiritual, environmental, physiological, social, and other systems as "agents" which play a part in a person's health.  A holistic model integrates the specific cause model and the systems model, and looks at both the disease and the systems in which the subject lives.  CAM care addresses physical, mental, and spiritual needs of patients.  It mobilizes the patient's capacity for self-healing, with the difference between "healing" and "curing" underscored.  It also places importance on the relationship between provider and patient.

With CAM therapy, outcomes can be more difficult to define, since treatments are individualized, and changes may be clinically subtle.  Non-clinical changes can be more important, such as a sense of peace or spiritual growth.  This situation presents challenges to the FDA structure.  Dr. White suggested developing questionnaires as one possible method for measuring improvements in well-being and awareness.  Some indirect measures are also available, such as adherence to and compliance with treatment, and measuring usage of other health care sources.  Qualitative research methods, such as the use of focus groups, are important in understanding how people experience the disease process.

Dr. White addressed some of the issues for CAM research.  Targeting a known and described condition is important to meet the needs of clinical trials.  The cultural context of CAM therapies needs to be understood when bringing them into a conventional healthcare setting.  Getting CAM practitioners to agree on a protocol has been difficult, due to the wide variation in complementary and alternative medicine.  The role of patient preference is an important issue, since belief in a certain treatment can affect a patient's willingness to accept randomization.

The Interactive Cases

The panel discussions served as a prelude to a unique interactive case study session.  Each participant was assigned to a breakout team for study of a case to identify critical issues that need to be considered in clinical trial design and implementation.  For a description of the seven cases studied and the composition of the study teams see Appendix 3.  The topics discussed included issues related to off-label use; surrogate end points, and drug/device combination products.  Other topics discussed were ethical issues when using human subjects, special statistical problems in dental clinical trials, and financial considerations in clinical trials.  The following table outlines and summarizes the rationale and main issues considered by each case.

INTERACTIVE CASES: ISSUES AND CONSIDERATIONS

Recommendations

Several outcomes related to clinical trials emerged:

Regulatory Domain
In the regulatory domain, the complexity involved in obtaining FDA approval of technologies that are both devices and drugs was initially seen as a problem.  But several teams presented strategies for addressing this issue.  The emphasis on early "informal" contact with FDA was uniformly welcomed and supported.  In addition, all teams emphasized the need for new well-defined guidelines for products that may require multi-center reviews. 

Economic Domain
In the economic area, the magnitude of the costs of clinical trials was a major theme.  The return on investment (ROI) was discussed relative to the size of the dental market.  One team explored the social and financial issues faced by several small companies attempting to pool their resources to form an alliance to perform clinical trials on a new product.    In their reports, each team reiterated the need to evaluate market potential, production costs, and competitive advantage prior to initiating an expensive clinical trial.  They also stressed that FDA and NIDCR should continue to work with industry representatives to facilitate clinical trials by standardizing criteria such that results are acceptable to both agencies and costly repetition is avoided.

The Importance of NIDCR/FDA Cooperation for Successful Clinical Trials
Overall, the presentations emphasized that successful clinical trials are critical to launch new products and that NIDCR should explore novel mechanisms to partner with industry to encourage industry investment in development of new clinical products.

Appendix 1 (Program) | Appendix 2 (Participant List) | Appendix 3 (Study Cases)