BTC6210, Quiz 3 (Weeks 6, 7, 8 Lecture + reading material)
IRB continuing review should include
***Review any Conflict of Interest, if reported or known *current informed consent documents and protocl *status report on the progress of the research *number of subjects enrolled *description of any adverse events or unanticipated problems *any withdrawal of subjects from the research *complaints about the research *summary of any recent literature *findings obtained thus far, including reports on multi-center trials *amendments or modification since the last review
Week 6 Reading: "Useless Pharmaceutica"
*12 year old research study of Neurontin, a seizure drug made by Pfizer *notable for how poorly it was conducted *it looked like a clinical trial, but as litigation documents have shown it was actually a marketing device known as a "seeding trial". These trials are not used to advance research and instead are used to make doctors familiar with a new drug. *many patients volunteer for research in the hope that the knowledge generated will benefit others. When a company deceives them into volunteering for a useless study, it cynically exploits their good will, undermining the cause of legitimate research everywhere.
Data safety Monitoring Plan (DSMP) and Data Safety Monitoring Board (DSMB) Requirements
*All NIH sponsored clinical trials are required to have a data monitoring plan (DSMP). DSMP=a written plan that describes how data safety and integrity will be monitored and maintained. This is usually submitted to IRB to review and approve. *NIH-sponsored trials with clinical endpoints have a DSMB *many industry sponsored studies have a DSMB *there's an FDA guidance document on it
Kefauver Harris Amendment (1962)
*Authorized regulations for investigational new drugs but did not require the submission of study plans, record keeping, or statements from investigators *Access to investigational drugs outside of clinical trials for treatment use only was not very formal *The only mandatory provision was that investigators had to obtain informed consent from every subject
Week 7 Reading: "Selective Reporting"
*Comparison of clinical trial registrations and their respective publications *Of the 203 RCT included, only 35% posted results in the registry *reporting of serious adverse events was largely inconsistent (SAE)
EAP Categories - Devices
*Compassionate Use (single patient/small group access)=Compassionate use is typically approved for individual patients, but may be approved to treat a small group. Prior FDA approval is needed before compassionate use occurs. *Treatment Use (larger group/more widespread use)= FDA will consider this expanded access under a Treatment IDE (21 CFR 812.36). An approved IDE specifies the max number of clinical sites and the max number of human subjects enrolled in a study. During course of the trial, if the data suggests the device is effective, then the trial may be expanded *Continued Access = the FDA may allow enrollment of subjects after the controlled clinical trial under an IDE has been completed and while the marketing application is being prepared by the sponsor or reviewed by FDA. The Continued Access Policy, which is applied after completion of the clinical trial, may be considered for any clinical investigation.
IRB Continuing Review Should Include
*Current informed consent document *current protocol or protocol summary *status report on the progress of the research *number of subjects enrolled *description of any adverse events or unanticipated problems *any withdrawal of subjects from the research *complaints about the research *summary of any recent literature *findings obtained thus far *amendments or modification since the last review *reports on multi-center trials *any other relevant information
Deviations
*Departure from procedures described in the IRB approved protocol: -protocol deviation=planned deviation from protocol as written usually with sponsor approval and IRB approval (ex: subject will not make scheduled clinic visit for labs and evaluation, etc. because of travel plans) -protocol exception=any protocol deviation that relates to eligibility criteria, ex: request to enroll subject who does not meet all eligibility criteria -protocol violation=a protocol deviation that was not prospectively approved by the IRB prior to its implementation (i.e., usually identified after the fact) **deviations can be described as major or minor
Types of Conflicts of Interest
*Individual (IRB members, research officials) *Institutional (financial holdings of the institution, decisions regarding research funding) *Financial (consulting fees, salary, IP rights, enrollment bonuses) *Professional (pressure to publish, career advancement)
IRB oversight (after approval)
*continued ethical evaluation of the research *monitoring of the research *monitoring of the informed consent process *analysis (as received) of new information, adverse events, and unanticipated problems involving risks to subjects and others *formal continuing review at intervals appropriate to the degree of risk and no less than annually
Week 6 reading: "Injury to Research Volunteers NEJM"
*eight healthy men enrolled in a trial under development by TeGenero. six assigned to drug, two received placebo. *trial conducted for TeGenero by Parexel a large CRO *6 volunteers were the first humans to receive TGN1412 *preclinical testing in rabbits and monkeys showed no signs of toxicity *after receiving injections the 6 volunteers became desperately ill, multiple organ failure, transferred to ICU. (cytokine release syndrome) *in this case: subjects were treated simultaneously without a reasonably long interval in between. this was a wrong choice *early safety data is considered proprietary (if similar drugs have been tested by other companies, could cross-reference this data to see issues beforehand)
Week 6 reading:"McGee Warning Letter"
*failed to fulfill the responsibilities of a clinical investigator a study utilizing an unlicensed biological investigational new drug violations: (21 CFR Part 312) 1. You failed to fulfill the general responsibilities of investigators 2. You failed to ensure that an investigation is conducted according the investigational plan (protocol) 3. You failed to obtain IRB approval prior to implementing protocol amendments or changes in the research activity 4. You failed to control the investigational drug 5. You failed to maintain adequate records of the disposition of the investigational drug
If a COI is identified, what do you do?
Disclosure is the most common strategy for dealing with COI. It's important to disclose COI to the investigator's institution, the IRB, and those to whom the results are reported (journals, sponsors, FDA, etc.) **COIs are not always unethical or unacceptable - they are sometimes unavoidable and in many cases can be appropriately managed
Preventing COI
Disclosure of any potential conflict, working with the institution, being honest and following the rules. Examples: *List any financial support you and your co-authors receive that might be construed as a conflict with your research aims *List any social or personal activities that may impact how you do your research *Examine any current or recent institutional relationships you may have that may be considered to impair your objectivity in your research *Examine and adhere to all the criteria provided by your preferred journal on what constitutes a conflict of interest and how authors should declare them
Human Subject Protection for EAP (expanded access)
Drugs in EAPs are investigational drugs and they are subject to the following requirements from 21 CFR: *Part 50-protection of human subjects (informed consent) *Part 56-institutional review board *Part 312-including clinical holds based on safety and reporting requirements (adverse event reports, annual reports)
1970s - 1980s (history of facilitating access to investigational therapies)
During the 70s through the 80s: *patient and disease advocates were actively advocating use of the newest drugs to treat AIDS patients *treatment IND and the parallel track protocol are used to expand access of investigational drugs to critically ill AIDS patients
Criteria for All Expanded Access (EAP), 21CFR312.305(a)
FDA must determine: 1. The patient or patients to be treated have a serious or immediately life threatening disease or condition that has no alternative therapy 2. The potential patient benefit justifies the potential risks of the treatment 3. Providing the investigational drug for the requested use will not interfere with the initiation, conduct, or completion of clinical investigations
1987 FDA revised...
FDA revised the IND regulations in part 312 (21 CFR part 312) *authorized access to investigational drugs for a broad population under a treatment protocol or treatment IND
Unanticipated problems involving risks to subjects or others (UPIRSO) REGULATIONS
Federal Regulations (45CFR46 and 21CFR56) requires the IRB to ensure that investigators promptly report "any unanticipated problems in involving risk to subjects or others" Federal regulatory guidance published by the OHRP states that it considers unanticipated problems in general to include any incident/experience/outcome that meets following criteria: 1)unexpected 2)related or possibly related to participation in research 3) suggests that the research places subjects at a greater risk of harm than previously anticipated
1997 FDAMA
Food and Drug Modernization Act *specific provisions concerning expanded access to investigational drugs for treatment use As a result of the FDAMA, an individual patient may obtain an investigational drug for treatment use when: *the patient's physician determines that the patient has no comparable or satisfactory alternative therapy *FDA determines that there is sufficient evidence of safety and effectiveness to support use of the investigational drug *FDA determines that providing investigational drug will not interfere with the initiation, conduct, or completion of clinical investigations to support marketing approval *the sponsor or clinical investigator submits information sufficient to satisfy the IND requirements
Research Misconduct (when does it occur)
Happens when a researcher fabricates or falsifies data, or plagiarizes information or ideas within a research report. The misconduct must be committed intentionally, and the allegation must be proven by sufficient evidence. The definition of misconduct can also extend to breaches of confidentiality and authorship/publication violations. Whistleblowers, or those reporting the misconduct, are obligated to act, yet may face serious consequences, such as reduction in research support, ostracism, lawsuits or termination
Management of Conflicts
Mechanisms that are used to avoid or manage conflicts: *public disclosure of financial interests *monitoring of research by independent reviewers *modification of the research plan *change of personnel or personnel responsibilities *divestment of the financial interest Note** The conflict of interest does not have to be eliminated. Depending on the potential outcome, the COI could be managed.
Selective Reporting bias
When results from scientific research are deliberately not fully or accurately reported, in order to suppress negative or undesirable findings. The end result is that the findings are not reproducible, because they have been skewed by bias during the analysis or writing stages. Happens in clinical trials when outcome data are collected but not reported, and when investigators do many analyses but report only the most favorable.
Possible DSMB Decisions
*continue w/ trial as planned *stop: safety problem *stop: efficacy established *stop: new knowledge (usually from other trials suggesting risks) *stop: futile. Trial unlikely to show a result *modify trial design If DSMBs are properly constituted they help to: ensure the safety of participants in a trial AND help the investigators to make sure that the maximum information is obtained from a trial.
Week 6 reading: "Death but one unintended consequence of gene therapy"
*Jesse Gelsinger story *wanted to help others overcome the same metabolic disorder he had *entered a gene-therapy trial *was the first person to die because of participation in gene-therapy research *Gelsinger had OTC deficiency, a metabolic disorder. His outcome was different because he had only partial OTC deficiency which he kept in check with a low protein diet and drugs *was given corrective OTC gene encased in a dose of attenuated cold virus, he died 4 days after receiving it. *issue with informed consent, he was not told that several other patients had experienced serious side effects *there was a conflict of interest. Wilson the director of the Penn Institute where Gelsinger was treated - owned stock in a company called Genovo that provided financing for the institute Result -> The New gene therapy clinical trial monitoring plan requires disclosure and clinical monitoring before a trial begins and clarifies what events need to be reported. Also FDA started to forbid investigators/team members who are involved in patient selection from holding stock/equity in companies sponsoring the trial
Continuing Review
*Serves the purpose of permitting the IRB the opportunity to substantively review the research after it has begun, subjects have been enrolled, and some experience has ben gained in the practice of this particular protocol *required to occur within one year (no grace period) *IRB must review all relevant materials *continuing review is opportunity to see what has happened once the research started *More than status reports should be reviewed: review must be substantive and meaningful
EAP Categories - drugs
*Single patient IND=treatment is generally limited to a single course of therapy for a specified duration unless FDA expressly authorizes multiple courses *intermediate-size patient population= fda may ask sponsor to consolidate expanded access under this section when the agency has received a significant number of requests for individual patient expanded access to an investigational drug for the same use *treatment IND or Treatment protocol = FDA may permit widespread treatment use of an investigational drug as Treatment Protocol under 21CFR312.320
Recommended Consent Form Language
*The informed consent document should disclose if the PI or any investigators have any conflicts of interest.
Benefits of Expanded Access
*access for patients with serious/life-threatening diseases who have no other alternatives *provides a measure of autonomy for patients *bridges the gap between the latter stages of product development and approval *can help foster development of additional uses of a drug *offers hope if there is no other available options
Week 7 Reading: "COI in Research How to Avoid COI in Research"
*all types of submissions to a journal, articles, review articles, opinion pieces, and editorials should be accompanied by a conflict of interest disclosure statement *the most common COI is financial ties *the most common non--financial COI are relationships or professional affiliations *full transparency is always the best course of action, and if in doubt disclose
Week 8 Reading: "Final Rule, Expanded Access to Investigational Drugs for Treatment Use - Federal Register" , 21CFR Parts 312 and 316
*amendment of regulations on access to investigational new drugs for the treatment of patients. clarifies existing regulations and adds new types of expanded access for treatment use *under the file rule: expanded access to investigational drugs for treatment use is available to individual patients, including in emergencies;intermediate size patient populations; and larger populations under a treatment protocol or treatment investigational new drug application (IND) *the final rule is intended to improve access to investigational drugs for patients with serious or immediately life threatening diseases or conditions who lack other therapeutic options and who may benefit from such therapies *the final rule amends FDA regulations by removing the current sections on treatment use of investigational drugs, revising clinical holds, and adding subpart I of part 312 on expanded access. *The final rule provides the following: -Criteria that must be met to authorize the expanded use -requirements for expanded access submissions -safeguards to protect patients and preserve the ability to develop meaningful data about treatment use
Week 8 Reading: "EUA" Emergency Use Authorization vs Full FDA approval
*an EUA is a tool the FDA can use to expedite the availability of medical products during a public health emergency *can only be granted when no adequate, approved, or available alternatives exist and when benefits outweigh the risks *EAU process differs from the full approval process: -shortened length of time vaccines patients followed post vaccination -full approval requires more data about the vaccine maker's processes and facilities and manufacturing plants
Unanticipated problems involving risks to subjects or others (UPIRSO)
*both the DHHS & FDA regulation requires that unanticipated problems involving risks to subjects or others be promptly reported to the IRB *what is it? An unanticipated problem is considered to be an event that is (1) unexpected given (a) the research procedures described in the protocol documents and (b) the characteristics of the participant population being studied (2) related or possibly related to involvement in the research, and (3) placing participants or others at a greater risk of harm than was previously expected
Week 7: "Responsibility of Applicants for Promoting Objectivity in Research" 42CFR50 and 45CFR94
*changes that expand and add transparency to Investigators' disclosure of significant financial interests (SFIs) *enhances regulatory compliance and effective institutional oversight and management of investigators' financial conflicts of interests as well as increase the HHS compliance oversight *high level: regulations are designed to promote objectivity in Public Health Service funded research *changes to 1995 regulations include: -amending the definition of SFI to have a minimum threshold of $5000. -excluding income from gov agencies or institutions of higher education *expanding investigator disclosure requirements to include SFIs that are related to an investigator's institutional responsibilities -enhancing the information on an FCOI reported by the institution to include the info under 1995 regulations plus the value of the financial interest or a statement that a value cannot be readily determined, the nature of the FCOI, and a description of how the FCOI relates to the PHS-funded research -before spending funds for PHS-supported research the institution shall post on a website information on the SFI of senior/key personnel that are related to the PHS-funded research and constitute a FCOI
Week 6 reading: "Unethical Clinical Trials during COVID"
*focus on clinical trials in Africa *in 2001, Pfizer has been accused over informed consent issues and unethical trial in Nigeria during the meningitis epidemic in 1996 *since COVID began, there was a push to develop a vaccine to protect us from the virus *identifying countries w/ weak clinical trial guidelines and policies could be preferred for unethical and fast clinical trials *responsibility of the governments to fully understand the risks of clinical trials on their populations *It is ethically unacceptable to leverage the lack of capabilities and poverty to satisfy our desire to understand scientific mechanisms and examine the effectiveness of drug and vaccine candidates *additional layers of clinical trials supervision from international organizations such as the WHO and the WMA could help to enforce the trial guidelines
21 CFR 312.300 (Subpart 1), 2009 [Expanded access today]
*improves access to investigational products for patients thru better understanding of what is accessible, and what is the process *streamline regulatory processes for EAPs
Week 7 Reading: "COI in Research - looking out for number one"
*increased interest in medical ethics *regulations often define a specific level of financial thresholds as acceptable or not *mostly repetitive content
Conflict of Interest (COI) Institutional Reporting
*is is important that researchers involved in human research DO NOT HAVE OR APPEAR TO HAVE a COI- including a financial interest - related to any of the studies in which they participate *federal regulations, state laws and institutional policies require that faculty members, employees, staff submit financial disclosure forms at the time that a proposal is submitted for funding *annual disclosure could be instituted as part of the internal compliance framework
Risks of early access
*limited information about safety carries risk *no benefits are guaranteed *potential risk of harm
Week 6 Reading: "Proposal to Debar"
*message sent by FDA *investigator in clinical trials used unlicensed biological and investigational new drugs *withdrawal of eligibility as clinical investigator to receive investigational new drugs violations: 1. You failed to fulfill the general responsibilities of investigators 2. You failed to ensure that an investigation is conducted according to the investigation plan (protocol) 3. You failed to obtain IRB approval prior to implementing protocol amendments or changes in the research activity 4. You failed to control the investigational drug
Changes found in new regulation (21 CFR 312.300)
*new subpart I consolidates treatment use into a separate subpart of the IND regulations *new subpart I contains all necessary information *describes the 3 categories of (individual, intermediate size, treatment IND/protocol) *describes the general criteria applicable to all categories of access and additional criteria that must be met for each Access Category *Describes the submission requirements *Describes the safeguards applicable to EAPs (ex: informed consent, IRB review, reporting requirements) *provides for possible access to drugs that have a risk evaluation and mitigation strategy (REMS) that restricts availability of the drug - for patients who do not meet REMS criteria
Week 7 reading: "Trial Publication after Registration"
*not all data elements were reported *industry was less likely to publish than other sources *conclusion: reporting of optional data elements varied and publication rates among completed trials registered within clinicaltrials.gov were low. Without greater attention to reporting of all data elements, the potential for clinical trials.gov to address selective publication of clinical trials will be limited.
Deviations well known example: Melanoma Vaccine Study
*numerous deviations from the approved study protocol (ended with research being suspended): -subjects enrolled w/o meeting all eligibility criteria -failed to evaluate subjects immune response at time points specified in the protocol -vaccine shipped to subjects for self-injection w/o prior IRB approval -failed to follow stopping rules for subjects showing disease progression -inadequate supervision of sponsor's manufacturing facilities
EAP and Therapeutic misconception
*possible overestimation of benefit *possible underestimation of risk *limited information *cost - drugs not covered by insurance
Week 6 Reading: "Statement of Cherlynn Mathias, RN"
*previous study coordinator at the University of Oklahoma. testify about experiences *realized almost immediately ineligible subjects were being enrolled *discovered several patients had been allowed to inject the vaccine (patient safety, also unsecured environment) *discovered the current version of the protocol had never been submitted to the IRB even though it had been in use for seven months *adverse events reporting was practically non-existent *threat to the research process and human subject protections is the lack of adequately trained research personnel
21 CFR 312.300 (Subpart I) high level
*prior approval from the FDA is required for every category of EAP *prior IRB review and approval with the exception of Emergency Use of investigational article
Week 8 Reading: "Challenge and ethical aspects of compassionate use"
*published by Indian Journal of Pharmacology *unapproved new drugs for compassionate use *compassionate use was important during COVID-19 crisis in order to manage the pandemic *compassionate use=expanded access *difficult to generalize guidelines regarding compassionate use in the whole world because of difference in country-specific drug access regulations and legal pathways *there is a lack of single definition of compassionate/expanded use programs all over the world with different nomenclature for such concerned programs in different countries
Revisions, Modifications, or Amendments
*require prospective approval by the IRB prior to being implemented *minor changes may be reviewed by the IRB using expedited review procedures IF -> research must be previously approved by IRB, change must be during the established approval period, OR must be reported to the full IRB
FDA oversees reporting of clinical trials through:
*requiring data submission to clinicaltrials.gov *data is to be reported within 12 months of study completion *progress of the study should be updated at least annually, if not every 6 months
Week 7 Reading: "Conflict of Interest in clinical drug trials"
*risk factor for scientific misconduct *COI can be defined as "a conflict between the private interests and official responsibilities of a person in a position of trust" *not all conflict of interest situations create scientific misconduct, but conflict of interest situations may increase the chance of scientific misconduct *violations of misconduct can include: designing studies to ensure a desired result, making statements not justified by the evidence, publishing only part of the evidence, suppression of research findings, and worst outright fraud with fabrication of evidence *company-funded research tends to favor that company's products *trial design can be skewed, purposefully using an inferior drug for comparison or using a higher dose of their own product *private physicians can be paid between $1000 to $5000 for each patient enrolled in a study *data analysis -? the data usually belongs to the sponsoring company and the company decides who sees how much of the data *substantial numbers of clinical trials are never reported in print, due to the results not favoring the drug being tested *writers can use different statistical measures to make drugs appear more efficacious
Could EAP affect subject enrollment?
*risk of low interest in controlled study *limited manufacturing capacity if drugs need to be manufactured for clinical trials and also for outside of research settings
Week 6 reading: "Seeding trial"
*seeding trials=clinical studies conducted by pharma companies for marketing purposes *used to promote drugs recently approved or under review by the FDA by encouraging prescribers to use these medications under the guise of participating as an investigator in a clinical trial *seeding trials are not illegal, but they are unethical *The STEPS trial used an uncontrolled and unblinded design to study gabapentin efficacy, safety, and tolerability, a questionable design - particularly for efficacy. *pharma sales reps were directly involved in collecting and recording individual subject trial data *used for promotion despite its stated scientific objective to examine safety, efficacy and tolerability of the drug
Week 7 Reading: "Publishing Clinical Trial Results: The Future Beckons"
*suggests how methods of reporting clinical trials could be improved and consider implications for trial sponsors and medical journals *information remains hard/expensive to access, scattered across many places, and difficult to synthesize *often times print is same as in physical journal, can be difficult to read *huge problem -> non-publication of negative trials and non-reporting of negative outcomes coupled w/ redundant publication of positive findings - which has led to systematic publication bias and can undermine the reliability of medical evidence *article suggests having trial registration designs publicly available (to both remove repeat publications and allows un-favorable negative trials to not remain hidden since they are already being tracked)
Week 6 Reading: "Clinical Trial Guidelines at Odds with U.S. Policy" 2008
*the World Medical Association (WMA) revised its ethics manifesto to include: sharper limits on the use of placebos and stronger language requesting that trial sponsors care for all participants after a trial is finished *in a new provision that's likely to provide controversial, WMA asks sponsors to register clinical trials in publicly available databases before recruiting the first subject *since its adoption in 1964 the Declaration of Helsinki has been amended five times
Adverse events (AE)
*the investigator obtains adverse events information from feedback from the study subjects, reports from medical care providers, observations by research staff, physical assessments, and medical records *definition=any unfavorable and unintended medical occurrence/sign, symptom or disease in a patient or clinical investigation subject administered a pharmaceutical product and which does not have a casual relationship w/ this treatment (reporting required under 21CFR312) *AE could be graded based on seriousness/severity
Week 6 reading: "Thousands of Indians die in unethical clinical trials"
*thousands of Indians have died in unethical clinical trials over the past decade *in only a small number of cases have pharma companies offered compensation for deaths *"the trials take advantage of loopholes in rules, loose oversight, and India's large population of poor people who are unaware of their rights as trial subjects" *clinical trials increased in 2005 when India relaxed its testing laws *ex: a man signed up for clinical trial without his consent, form was in english which he could barely understand, but in his own language doctors told him he would be treated free of charge (failure of informed consent) *after the man's son complained the doctor responsible was suspended for only 3 months *doctors and clinicians running these trials had frequently been sent on trips overseas or been paid out of process by pharma companies
How do patients find EAP?
*through their healthcare provider *internet (clinicaltrials.gov, patient organizations, patient forums) *other patients (support groups, clinic visits, conferences and symposiums)
Issues for the Sponsor (when using EAP)
*time consuming *not enough capacity to produce an investigational drug to meet the additional demand *communicating issues with providers outside of research/investigator network *challenge to train individual physicians on regulatory requirements, processes, and procedures *would data from EAP affect NDA review or investors?
Issues with EAP
*who pays for investigational drugs? (manufacturers? insurance carriers? patients?) *risk to physicians *IRB issues: how difficult is IRB to secure? Who pays for the cost of review?
How does the FDA ensure Data Integrity and Human Subject Protection?
Bioresearch Monitoring Program (BIMO: *protect the rights, safety, and welfare of subjects in FDA-regulated trials *determine the accuracy and reliability of clinical trial data submitted to the FDA in support of research or marketing applications *assess compliance with FDA's regulations governing the conduct of clinical trials, including those for informed consent and ethical review summary BIMO program: comprehensive program of on-site inspections and data audits designed to monitor all aspects of the conduct and reporting of FDA-regulated research.
Serious Adverse Event (SAE)
Any AE that at any dose: *results in death *is life threatening (requires hospitalization, results in persistent disability, birth defect, important medical event, etc.)
Conflict of Interest
Any situation in which financial, professional, or personal obligations may compromise or appear to compromise professional judgment in designing, conducting, analyzing, reporting, or supporting research. Note: If there is a perception that the situation affects professional judgment=there is a conflict
Data and Safety Monitoring (DSMBs vs data and safety monitoring plans)
Can be done by data and safety monitoring boards (DSMBs). They are an important mechanism for overseeing clinical trials. Consist of committees of experts (scientists, physicians, statisticians, etc) and perform ongoing monitoring of the data and safety of interventional trials. DSMBs are REQUIRED for multi-center clinical trials involving interventions that involve potential risks to subjects, which generally involve Phase III clinical trials. Basically involve trials with substantial uncertainty about safety (ex:gene therapy) However, data and safety monitoring plans (not DSMBs) are required for phase I and phase II clinical trials.
Why are COI a problem?
Conflicts of interest have the potential to skew several aspects of research, including how a study is designed, how data is collected, processed, and published, and who is involved in the work. This could also lead to research misconduct.
Publishing ethics
Cover a wide range of issues: *dual submission *authorship disputes *bias in peer review *breaches of confidentiality in peer review
DSMB Meeting Formats (3)
Open session, closed session, and executive session (DSMB only) Open session: progress report using open data, sponsor (ex:NIH), executive committee, protocol chairs, DSMB and unblinded statisticians Closed session: blinded data by treatment group. DSMB and unblinded statisticians only Executive session=DSMB only
Research Integrity
Research integrity = conducting research according to the highest professional and ethical standards, so that the results are trustworthy. It concerns the behavior of researchers at all stages of the research life-cycle *research integrity can be confused w/ research ethics and publishing ethics
History of facilitating access to investigational therapies
Started with Federal Food, Drug, and Cosmetic Act in 1938 *contained one brief section, labeled 505(i) *labeled "for investigational use only" *delivered only to and used by experts *adequate facilities for investigation *statement from the investigator indicating that the drug would be used solely for investigational purposes until fully licensed
Week 7 Reading: " Final Rule Sunshine Act - Conflicts of Interest in Academic Medicine"
Summary: *This final rule will require manufacturers of drugs, devices, biologicals, or medical supplies covered by Medicare, Medicaid, or the Children's Health Insurance Program (CHIP) to report annually to the Secretary certain payments or transfers of value provided to physicians or teaching hospitals ("covered recipients"). *In addition- applicable manufacturers and applicable group purchasing organizations (GPOs) are required to report annually certain physician ownership or investment interests. The Secretary is required to publish applicable manufacturers' and applicable GPO' submitted payment and ownership information on a public Web site. Effective April 9, 2013.
Role of DSMB
The primary responsibilities of the DSMB are to periodically review and evaluate the accumulated study data for participant safety, study conduct and progress, and when appropriate, efficacy, and make recommendations to sponsor and investigator concerning the continuation, modification, or termination of the trial. *Monitor data throughout a trial (only group that has access to unblinded data before the end of the study) *Analyzes data by treatment arm (are there any concerns about safety? is there already enough proof that the intervention works?) *Other considerations: New evidence that might be relevant to the trial. Practicalities: is it still feasible to continue?
Expanded Access
Use of an investigational drug of biologic to treat a patient with a serious disease or condition who does not have comparable or satisfactory alternative therapies to treat the disease or condition (in contrast with investigational drug in clinical trial where the primary intent is research)
Today's definition of expanded access ("compassionate use")
Use of investigational new drugs and approved drugs where availability is limited by a risk evaluation and mitigation strategy (REMS) when the primary purpose is to diagnose, monitor, or treat a patient's disease or condition
Research ethics
specifically concerned with the ethical issues which may arise when conducting research involving animals or human subjects