Analysis of Information Submitted by Clinical Trial Sponsors regarding the Safety of Investigational Drugs

Investigational drugs are regulated by the Food and Drug Administration (FDA) and are not available for widespread patient use. They are screened and evaluated extensively before they are administered to humans in clinical trials. The clinical development process is divided into three phases: phase I, II, and III. Protocols for the investigational agent in each of these phases must be approved by an institutional review board and the patient must be informed of the risks of the study and sign an informed consent document. Once adequate clinical data are collected and analyzed, the information is submitted to the FDA for their review and approval for marketing. Prior to that approval, the FDA may approve broader distribution of the drug for specific indications under a Treatment Investigational New Drug (IND) or the National Cancer Institute's (NCI) group C mechanism. Pharmacists can play a unique role during development of the Treatment IND by contributing to design of the protocol and screening patient qualifications. The investigator of the clinical trial has responsibility for the conduct of the clinical trial and must comply with FDA regulations and sponsor policies. This is a US government work. There are no restrictions on its use.

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Prediction of factors affecting clinical trial accrual at Cancer Therapy and Research Center, San Antonio.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e18207 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e18207-e18207

Author(s):

Praveena Iruku

Keyword(s):

Clinical Trial ◽

Univariate Analysis ◽

New Drugs ◽

Disease Category ◽

Chi Square ◽

Significance Level ◽

Factors Affecting ◽

Exact Test ◽

Investigational Drugs ◽

Clinical Trial Accrual

e18207 Background: Oncology is a very rapidly emerging science with need for more investigational drugs. It is highly essential to accrue patients into clinical trials to develop new drugs. According to the available data, about 38 % of the CTEP/NCI supporting oncology trials close due to inadequate accrual. We here by present a retrospective analysis of factors which affect clinical trial accrual in our institution. Methods: Eligible studies included treatment and supportive care intervention studies either open or closed to accrual between 09/1999 and 012/2015 at our center. Data abstracted includes coordinating group, sponsor type, presence of competing trials, trial phase, disease category, single institutional study, author, primary purpose of the study, interventional modality, targeted therapy, advanced disease, randomization, presence of placebo, rare cancer category and new investigational agents. Successful clinical trial accrual was defined as accruing 4 or more patients. Statistical analysis was performed in the statistic software R (R Foundation for Statistical Computing, Vienna, Austria). We used Chi-square test and Fisher’s exact test. The significance level was set to alpha = 0.05. Results: Retrospective univariate analysis at our institution showed that the variables significantly associated with clinical accrual are Authored by principal investigator, type of sponsor, phase of the trial and number of interventions in the study. Using a random forest model with the above mentioned predictors, we computed an AUC of 64.1 % . We have also developed a histogram of predictions which has identified atleast 5 studies with an 80% failure probability to accrue. Conclusions: Clinical trial accrual is absolutely necessary for development of investigational drugs and progress of research in Hematology/Oncology especially with the rise in incidence of many malignancies. We have identified a few factors that may impact accrual in our institution, and we propose to prospectively validate it in our future endeavor. The major limitations of our study are its retrospective nature and being a single site analysis.

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The Practice of Pharmaceutics and the Obligation to Expand Access to Investigational Drugs

The Journal of Medicine and Philosophy A Forum for Bioethics and Philosophy of Medicine ◽

10.1093/jmp/jhz038 ◽

2019 ◽

Vol 45 (2) ◽

pp. 193-211 ◽

Cited By ~ 1

Author(s):

Michael Buckley ◽

Collin O’neil

Keyword(s):

Clinical Trial ◽

Moral Obligation ◽

Future Research ◽

Pharmaceutical Companies ◽

Expanded Access ◽

Moral Permissibility ◽

Trial Process ◽

Investigational Drugs ◽

Potential Impact ◽

Pharmaceutical Practice

Abstract Do pharmaceutical companies have a moral obligation to expand access to investigational drugs to patients outside the clinical trial? One reason for thinking they do not is that expanded access programs might negatively affect the clinical trial process. This potential impact creates dilemmas for practitioners who nevertheless acknowledge some moral reason for expanding access. Bioethicists have explained these reasons in terms of beneficence, compassion, or a principle of rescue, but their arguments have been limited to questions of moral permissibility, leaving for future research the question of whether expanded access is morally obligatory. We take up this further question and argue that pharmaceutical companies have a moral obligation to expand access. Our defense is not based on beneficence, compassion, or rescue, but instead on a reciprocal moral expectation resulting from existing social commitments that help ensure a robust pharmaceutical practice within the broader healthcare system. Our aim is to give this obligation, along with several others, a coherent and plausible structure within the wider clinical trial process so that one might better explain the sources of the dilemmas and their possible resolutions.

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Providing Hope: Developing a Viable Regulatory Framework for Providing Terminally Ill Patients With Adequate Access to Investigational Drugs

University of Pittsburgh Law Review ◽

10.5195/lawreview.2008.124 ◽

2008 ◽

Vol 70 (1) ◽

Author(s):

James P. Sikora

Keyword(s):

Clinical Trial ◽

Body Temperature ◽

Life Support ◽

Terminally Ill ◽

Regulatory Framework ◽

Her Family ◽

Investigational Treatment ◽

Investigational Drugs ◽

Common Feeling ◽

To Receive

“If I die . . . I want my children to know I did everything I could.” This is a common feeling among terminally ill individuals facing death. This desire to exhaust every option often causes people to fight to receive potentially toxic and dangerous treatments that are still in the investigational phase if the treatment provides even a glimmer of hope for survival or improvement in condition. Investigational treatments, however, expose patients to myriad risks that can be difficult to predict. Jolee Mohr’s mysterious death provides a sad illustration of the dangers of investigational drugs. Mrs. Mohr’s physician recruited her for a clinical trial to test the safety of an investigational arthritis treatment. After she received the investigational treatment, Mrs. Mohr experienced intractable vomiting and increased body temperature. She subsequently slipped into unconsciousness, and her family made the decision to remove life support after doctors confirmed that she had no hope of recovery.

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Novel Biospecific Agents for the Treatment of Myelodysplastic Syndromes

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2003.0040 ◽

2003 ◽

Vol 1 (4) ◽

pp. 473-480 ◽

Cited By ~ 1

Author(s):

Jason Gotlib ◽

Peter L. Greenberg

Keyword(s):

Clinical Trial ◽

Supportive Care ◽

Myelodysplastic Syndromes ◽

High Intensity ◽

Mechanisms Of Action ◽

Therapeutic Approaches ◽

Low Intensity ◽

Investigational Drugs ◽

Trial Testing ◽

Biologic Response

Levels of treatment for patients with myelodysplastic syndromes (MDS) fall within 3 broad categories: supportive care, low- and high-intensity therapy. Most approaches remain experimental, and supportive care remains the standard of treatment in MDS. In parallel with the growing knowledge of the multiple pathobiologic abnormalities in MDS, increasing numbers of low-intensity, biospecific agents that target these pathogenetic lesions have entered clinical trial testing. Although the term “biospecific” has been applied to many of these investigational drugs, they often exert pleiotropic effects, many of which remain to be identified. An ongoing challenge will be to more fully characterize the mechanisms of action of these drugs and to characterize biologic correlates of response. With these data in hand, it will be increasingly feasible to treat patients with combinations of biospecific drugs with non-overlapping actions and toxicities, a therapeutic approach that is likely required to effectively overcome the barriers posed by the biologic heterogeneity of MDS. This review focuses on recent therapeutic approaches using such biologic response modifiers to treat MDS.

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Appraising Harm in Phase I Trials: Healthy Volunteers' Accounts of Adverse Events

The Journal of Law Medicine & Ethics ◽

10.1177/1073110519857289 ◽

2019 ◽

Vol 47 (2) ◽

pp. 323-333 ◽

Cited By ~ 1

Author(s):

Lisa McManus ◽

Arlene Davis ◽

Rebecca L. Forcier ◽

Jill A. Fisher

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Adverse Events ◽

Phase I ◽

Healthy Volunteers ◽

Trial Participation ◽

Trial Participant ◽

Phase I Trials ◽

Investigational Drugs ◽

Motivation To Participate

While risk of harm is an important focus for whether clinical research on humans can and should proceed, there is uncertainty about what constitutes harm to a trial participant. In Phase I trials on healthy volunteers, the purpose of the research is to document and measure safety concerns associated with investigational drugs, and participants are financially compensated for their enrollment in these studies. In this article, we investigate how characterizations of harm are narrated by healthy volunteers in the context of the adverse events (AEs) they experience during clinical trials. Drawing upon qualitative research, we find that participants largely minimize, deny, or re-attribute the cause of these AEs. We illustrate how participants' interpretations of AEs may be shaped both by the clinical trial environment and their economic motivation to participate. While these narratives are emblematic of the larger ambiguity surrounding harm in the context of clinical trial participation, we argue that these interpretations also problematically maintain the narrative of the safety of clinical trials, the ethics of testing investigational drugs on healthy people, and the rigor of data collected in the specter of such ambiguity.

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Investigators and Clinical Trial Subjects for Medication Counseling Categories of Investigational Drugs: a Survey

Journal of Korean Society of Health-System Pharmacists ◽

10.32429/jkshp.2017.34.1.003 ◽

2017 ◽

Vol 34 (1) ◽

pp. 45-53

Author(s):

유소현 ◽

나현오 ◽

한옥연 ◽

김유경 ◽

이정선

Keyword(s):

Clinical Trial ◽

Medication Counseling ◽

Investigational Drugs

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Ethical dimensions in randomized trials and off-label use of investigational drugs for COVID-19 treatment

Clinical Ethics ◽

10.1177/14777509211011431 ◽

2021 ◽

pp. 147775092110114

Author(s):

Pooja Dhupkar ◽

Seema Mukherjee

Keyword(s):

Clinical Trial ◽

Randomized Clinical Trial ◽

Randomized Clinical Trials ◽

Ethical Issues ◽

Off Label Use ◽

Off Label ◽

Investigational Drugs ◽

Number Of Patients ◽

The Impact ◽

Label Use

Coronavirus disease 2019 (COVID-19) is a fast-developing viral pandemic spreading across the globe. Due to lack of availability of proven medicines against COVID-19, physicians have resorted to treatments through large trials of investigational drugs with poor evidence or those used for similar diseases. Large trials randomize 100–500+ patients at multiple hospitals in different countries to either receive these drugs or standard treatment. In order to expedite the process, some regulatory agencies had also given permission to use drugs approved for other diseases, despite a lack of evidence of efficacy in COVID-19. In this review, we highlight the potential ethical issues that should be addressed during the use of investigational drugs with little prior evidence as a treatment options during a pandemic. We discuss the impact of design of randomized clinical trials using LOTUS trial as an example and that of off-label use of drugs like chloroquine/hydroxychloroquine (CQ/HQ) on the safety of patients during COVID-19. We conclude that the adaptive randomized clinical trial designs offer a flexible and efficient approach, enabling patients to quickly switch to successful treatments, while minimizing the number of patients on standard of care. Randomized clinical trial design should consider blinding of investigators and only representative patients who can provide consent should be included. We also conclude the emergency approvals of drugs should be carefully issued and off-label use should be restricted in pandemics. Streamlined regulatory guidelines for emergency drug use in a pandemic can also help in providing benefit and minimizing harm to patients in the future.

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