CASE 1
TEAM LEADER: BRUCE PIHLSTROM
TITLE: THE SCOPE OF IRB AND UNIVERSITY JURISDICTIONS IN THE DESIGN OF CLINICAL TRIALS
PURPOSE: TO EXPLORE CONSEQUENCES OF NIH/FDA POLICIES ON RESEARCH WITH HUMAN SUBJECTS
ROLE/POSITION OF PRIMARY DECISION MAKER: PROFESSOR OF PERIODONTICS AND PRINCIPAL INVESTIGATOR OF THE STUDY
REFERENCES:
Angell, M. Is Academic Medicine for Sale? N Engl J Med 2000, May 18, 342 (20): 1516-18.
Conflict of Interest: NEJM Admits Breaking its Own Tough Rules. Science, Vol 287, 3 March, 2000.
Press E., and Washburn J. The Kept University, The Atlantic Monthly, March 2000. P. 39-54.
See page 42. Quote by Mildred Chou.
"When you have so many scientists on Boards of companies or doing sponsored research, you start to wonder. How are these studies being designed? What kinds of research questions are being raised? What kinds aren't being raised?"
Other references:
Code of Federal Regulations
42 CFR Part 50
Subpart F: 45 CFR Part 94.
National Science Foundation: 60 CFR 35820
21 CFR Part 54 (effective Feb 1999)
FDA Regs.
CASE: Prior to the initiation of a trial of the safety and efficacy of a new product or intervention, approval of the protocol by an institutional review board (IRB) is usually required. There are exceptions. The regulations governing these exceptions are sometimes difficult to interpret and can present problems concerning the IRB’s jurisdiction and University authority.
As a professor of periodontics, you have developed a treatment for periodontitis and founded Periovent, a start up company located adjacent to the University, to initiate a clinical trial on this new product. The trial is to be paid for entirely by the company and will be conducted at the University’s dental clinic. You enroll subjects locally and attempt to begin the study when your department head informs you that you must obtain IRB approval. You argue that because this study is not funded by federal grants, the IRB need not be involved.
Your arguments are not accepted, so you submit the protocol to the IRB. Shortly thereafter, the IRB disapproves your proposal, citing the absence of an IND and failure to comply with NIH Human Subject guidelines. In addition, the University’s Conflict of Interest Review Committee raised questions concerning your involvement in the study.
Discuss the issues raised by this case concerning the actions of the IRB and the University. Comment on the location of the study, the funding source the source of subjects. Also, discuss why your involvement in this study might pose a conflict of interest and suggest how this conflict might be managed.
CASE 2
TEAM LEADER: FRED EICHMILLER
TITLE: CLINICAL TRIAL ISSUES FOR A PRODUCT THAT IS SUBSTANTIALLY EQUIVALENT
PURPOSE: TO EXPLORE DEFINITION AND INTERPRETATION OF SUBSTANTIAL EQUIVALENCE
ROLE/POSITION OF PRIMARY DECISION MAKER: DIRECTOR OF NEW PRODUCT DEVELOPMENT
CASE: To bring a device to market requires FDA clearance, most often after submission of a pre-marketing application (510k). Many class I products are exempt from 510k clearance. The 510(k) process requires that the sponsor demonstrate that the product is substantially equivalent to one previously cleared. If the product is not substantially equivalent to a previously marketed product, it would require a PMA (Pre-market Approval Application) that includes clinical data. In addition, if the product crosses FDA Center jurisdictions, it may be considered as a combination product that would require collaborative review by several FDA Centers.
Your company has developed an intra-oral magnetic device by which the magnetic field controls drug delivery. You submit an application requesting 510(k) clearance of the device because it generates magnetic fields similar to denture retaining magnets that are class II medical devices. You argue that your device is substantially equivalent to denture retaining magnets in that they generate an in situ magnetic field and, therefore, should be approved for marketing via the 510(k) process with inclusion of relevant clinical drug delivery data.
For a product such as this, the FDA would require drug and device input and the product would be considered as a combination product. The technology is substantially different from previously cleared drug delivery systems and raises new questions from the device perspective and the drug perspective, such as: the efficacy of the drug in a new delivery system and the effect of the magnetic field on patients. Also, how would drug/device clinical trial issues be consolidated? How could you facilitate interaction between the FDA’s Center for drugs and its Center for devices? Whom would you contact at FDA and what pre-planning and initial information would be required?
CASE 3
TEAM LEADER: TIM DE ROUEN
TITLE: BIOSTATISTICAL ISSUES IN THE DESIGN OF CLINICAL TRIALS
PURPOSE: TO EXAMINE CLINICAL DESIGN CRITERIA FOR COMBINATORIAL AND OFF-LABEL PRODUCTS
ROLE/POSITION OF THE PRIMARY DECISION MAKER: PROFESSOR OF BIOSTATISTICS AND CO-INVESTIGATOR ON A RESEARCH PROPOSAL
CASE: The biostatistical design of a clinical trial is often crucial to acceptance of the results of that trial by the FDA. The correct design, however, can become complex when a product contains more than one element such as a device and a drug. Because such combinatorial products cross FDA Center jurisdictional lines they may pose problems for both the FDA and the investigator/applicant.
A Professor of Biostatistics is asked to participate in a study by a dental colleague at a dental school. The product, Orastatin, was developed as an intervention for periodontitis. The treatment involves the intra-oral insertion of a device impregnated with an FDA-approved antibiotic. The antibiotic is slowly released from the device and is designed to act as a vasodilator, not as an anti-microbial.
The trial design drafted by the clinician involves studies of 4 treated and untreated test sites in each of 10 adult patients. The study design is centered on a comparison between the treated and untreated sites of each patient. In discussions with the investigator, the biostatistician indicates that the sample size may be too small and, in addition, he is uncertain that meaningful conclusions can be drawn from comparing sites within individual patients. The clinician argues that the disease is site and patient specific and therefore such data would be meaningful.
Discuss the issues that arise when designing clinical trials with small number of subjects, using multiple sites within each patient, and making intra-patient comparisons. Also discuss the issues (statistical and otherwise) that arise for a combinatorial product, for example one that contains both a device and a drug/biological. Especially consider what is required in meeting clinical design criteria of the several FDA Centers. Discuss the added complexity that occurs when a pharmaceutical approved for one purpose is used for another.
CASE 4
TEAM LEADER: RALPH GREEN
TITLE: SELECTION OF AN ENDPOINT FOR CLINICAL TRIALS OF A PRODUCT FOR ORAL MUCOSITIS
PURPOSE: TO EXPLORE ISSUES AFFECTING CLINICAL TRIAL DESIGN
ROLE/POSITION OF PRIMARY DECISION MAKER: DIRECTOR OF NEW PRODUCT DEVELOPMENT
CASE: Your company is developing a product for oral mucositis associated with cancer chemotherapy or radiotherapy. There is an urgent need to develop such a product because mucositis is a dose-limiting toxicity in cancer therapy. You know that this is an area of clinical research that is of interest to many companies and you want very much to get your product to market first. Because there are no products approved for oral mucositis, it is not clear what endpoint you should chose for your pivotal clinical trials.
What are the issues to consider in choosing an endpoint? Does your product have ingredients that require toxicity testing? Is the endpoint time based? Is it healing based? Is pain reduction the final endpoint? Will your product need a topical anesthetic to relieve pain during the healing process?
What is the bioactivity of the active ingredients? Can a placebo without the active ingredient be prepared? Has a drug interactivity profile with chemotherapeutic agents been developed? Will the IRB process require a lengthy review? Can 95 to 99 % confidence levels be reached for your endpoint?
How does FDA look at endpoints for pivotal trials? Can you financially support randomized trials at multiple sites? Will sites outside the United States be required?
CASE 5
TEAM LEADER: GEORGE WILKE
TITLE: DEVELOPING A PLAN FOR SEVERAL DENTAL COMPANIES TO POOL RESOURCES TO BRING A NEW PRODUCT TO THE DENTAL MARKET.
PURPOSE: TO DEVELOP A STRATEGIC ALLIANCE FOR SEVERAL SMALL COMPANIES TO JOINTLY DEVELOP AND BRING A NEW PRODUCT TO THE DENTAL MARKET.
ROLE/POSITION OF PRIMARY DECISION MAKER: PRESIDENT AND CEO OF A COMPANY THAT MANUFACTURES DENTAL FILES FOR ENDODONTICS.
CASE: Your Company has 25 employees and sales of 2 million dollars/yr. For the last several years, sales have been good and you find the company with excess cash that you would like to use for development of a new product. At a recent DMA/NIDCR Entrepreneurial Venture Fair, you were attracted to a presentation of a new product to stimulate the growth of dentin and believed that it would be an excellent addition to your product line.
A detailed discussion with your Director of New Products revealed that bringing this product to market will be prohibitively costly and time consuming. He suggested that you approach several other dental manufacturers with the idea of forming a partnership to bring the product to market. You accept his advice and convince five other small companies to form Strategic Alliance, Inc. for this purpose.
Describe how Strategic Alliance, Inc. would function. What FDA issues face the alliance in setting up clinical trials at a university clinic or with a contract research organization? In particular, what liability issues face the alliance? What opportunities and limitations are there for Strategic Alliance, Inc. to obtain funding through NIH SBIR/STTR or CRADA mechanisms?
CASE 7
TEAM LEADERS: MATT DOYLE and ROY PAGE
TITLE: CONSIDERATIONS FOR RAPID APPROVAL OF NEW USE OF AN APPROVED DRUG
PURPOSE: TO EXPLORE CONSIDERATIONS, FROM PERSPECTIVE OF VARIOUS STAKEHOLDERS, ASSOCIATED WITH THE RAPID DEVELOPMENT AND MARKETING OF A NEW DENTAL THERAPUETIC AGENT.
ROLE/POSITION OF PRIMARY DECISION MAKER: DIRECTOR OF PRODUCT DEVELOPMENT
CASE: Your Company has licensed the rights to develop an already marketed product for a new indication, treatment of rapidly progressive periodontitis used adjunctively with dental scaling and root planing. The approved product is a topical oral formulation, marketed as a rub-on or subgingival gel, and you intend to market a rinse formulation. The product has been studied to a limited degree as a rinse for periodontitis, but it is not marketed anywhere. Your company has limited funding for this project and the CEO would like to go directly to Phase 3 clinical trials. You are concerned about proceeding with limited information on dose ranging, efficacy in periodontitis, stability of the rinse formulation, and related issues.
What are the risks in proceeding directly to Phase 3? What could you do to minimize the risks? Are earlier data from prior studies of the marketed product sufficient or relevant to support the proposed Phase 3 study? Can the most efficacious dose from the prior dose response trial be selected to formulate a bioequivalent rinse for the Phase 3 trials? Would pharmacokinetic measurements in crevicular fluid, defining absorption, distribution and elimination of the rinse formulation, be sufficient to establish oral bioequivalence? Are the scaling and planing adjuncts required for the Phase 3 trial? Assuming effectiveness in the Phase 3 study, would one pivotal trial be sufficient for FDA approval?
CASE 8
TEAM LEADERS: MARIA RYAN and OTIS BOUWMA
TITLE: CLINICAL TRIALS OF A DENTAL PRODUCT THAT PRODUCES UNEXPECTED SIDE EFFECTS.
PURPOSE: TO CONSIDER CLINICAL DESIGN IMPLICATIONS OF ORAL PRODUCTS WITH POTENTIAL SYSTEMIC INFLUENCES
ROLE/POSITION OF PRIMARY DECISION MAKER: GENERAL DENTIST PARTICIPATING IN AN FDA APPROVED CLINICAL TRIAL
CASE: As a general dentist practicing in a small town, you have been asked by a dental manufacturing company to participate in a clinical trial of Orapack, a product for post-extraction treatment. The dry foam product is impregnated with an antibiotic and is designed to reduce infections at extraction sites. The foam and the antibiotic have been approved for use by the FDA and are on the market as separate products. The FDA has approved the clinical trial protocol.
The protocol calls for you to pack the socket with Orapack immediately after extraction. Four days after extracting a second molar on a 27 yr old male and placing the Orapack, the patient’s physician called to notify you that your patient was admitted to the hospital with rectal bleeding. After physical examination and biopsy, the patient was diagnosed with inflammatory bowel disease and possible ulcerative colitis. Further laboratory analysis revealed the presence of the parasite Cryptosporidium in the patients stool and Cryptosporidiosis was listed as an additional diagnosis. The patient’s history revealed that he recently returned from a visit to South America. The consensus of the medical staff was that the patient contracted Cryptosporidiosis from contaminated drinking water and that the antibiotic absorbed systemically from the extraction socket exacerbated the Cryptosporidial infection by altering the microbial flora of the intestinal tract.
This untoward side effect of the antibiotic in the Orapack preparation has raised several issues for the sponsoring company and for you, including possible financial liability. A careful reading of the product inserts for the dry foam and the antibiotic revealed no mention of excluded use of either product in patients with Cryptosporidiosis. In addition, the clinical trial protocol that was developed with, and approved by, the FDA made no mention of excluding patients with Cryptosporidiosis from the study.
The company informs the FDA of the untoward result of Orapack and the FDA must decide on a course of action. Should the study be terminated? Under what conditions could the study be continued? Should a warning be added to the product insert? The study has been underway for three years and this is the first untoward result. Can the company use any of the previous results of the clinical trial? What are the liability issues that you, the company and the FDA may encounter?