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Clinical Trial Designs

Timeline of various approval tracks and research phases in the US

Graph credit: Kernsters – Graph created based on information provided in Scientific American article, “Faster Evaluation of Vital Drugs“, CC BY-SA 3.0, https://en.wikipedia.org/w/index.php?curid=39972696

 

 

Clinical trials are experiments or observations done in clinical research. Such prospective biomedical or behavioral research studies on human participants are designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietary choices, dietary supplements, and medical 1) ___) and known interventions that warrant further study and comparison. Clinical trials generate data on safety and efficacy. They are conducted only after they have received health authority/ethics committee approval in the country where approval of the therapy is sought. These authorities are responsible for vetting the risk/2) ___ratio of the trial – their approval does not mean that the therapy is ‘safe’ or effective, only that the trial may be conducted.

 

Depending on product type and development stage, investigators initially enroll volunteers or patients into small pilot studies, and subsequently conduct progressively larger scale comparative 3) ___. Clinical trials can vary in size and cost, and they can involve a single research center or multiple centers, in one country or in multiple countries. Clinical study design aims to ensure the scientific validity and reproducibility of the results. Costs for clinical trials can be in the millions. The sponsor may be a governmental organization or a pharmaceutical, biotechnology or medical device company. Certain functions necessary to the trial, such as monitoring and lab work, may be managed by an outsourced partner, such as a (CRO) contract 4) ___ organization or a central laboratory.

 

An adaptive clinical trial is a clinical trial that evaluates a medical device or treatment by observing participant outcomes (and possibly other measures, such as side-5) ___) on a prescribed schedule, and modifying parameters of the trial protocol in accord with those observations. The adaptation process generally continues throughout the trial, as prescribed in the trial protocol. Modifications may include dosage, sample size, drug undergoing trial, patient selection criteria and “cocktail“ mix. In some cases, trials have become an ongoing process that regularly adds and drops therapies and patient groups as more information is gained. Importantly, the trial protocol is set before the trial begins; the protocol pre-specifies the adaptation schedule and processes. The aim of an adaptive trial is to more quickly identify drugs or devices that have a therapeutic effect, and to zero in on patient populations for whom the drug is appropriate. A key modification is to adjust 6) ___ levels. Traditionally, non-adverse patient reactions are not considered until a trial is completed.

 

In 2004, a Strategic Path Initiative was introduced by the United States’ FDA (Food and 7) ___ Administration) to modify the way drugs travel from lab to market. This initiative aimed at dealing with the high attrition levels observed in the clinical phase. It also attempted to offer flexibility to investigators to find the optimal clinical benefit without affecting the study’s validity. Adaptive clinical trials initially came under this regime. The FDA issued draft guidance on adaptive trial design in 2010. In 2012, the President’s Council of Advisors on Science and Technology (PCAST) recommended that FDA “run pilot projects to explore adaptive approval mechanisms to generate evidence across the lifecycle of a drug from the premarket through the 8) ___ phase.“ While not specifically related to clinical trials, the Council also recommended that FDA “make full use of accelerated approval for all drugs meeting the statutory standard of addressing an unmet need for a serious or life threatening disease, and demonstrating an impact on a clinical endpoint other than survival or irreversible morbidity, or on a surrogate endpoint, likely to predict clinical benefit.“

 

In the 2007-2009 period, the Department of Biostatistics at the M. D. Anderson Cancer Center was running 89 Bayesian adaptive trials, 36% of the total designed by the faculty. The FDA adaptive trial design guidance is a 50-page document covering wide-ranging and important topics “such as what aspects of adaptive design trials (i.e., clinical, statistical, regulatory) call for special consideration, when to interact with FDA while planning and conducting adaptive design studies, what information to include in the adaptive design for FDA review, and issues to consider in the evaluation of a completed adaptive design study.“ Attempts have been made to excerpt the guidance and make it more accessible.

 

According to FDA guidelines, an adaptive Bayesian clinical trial can involve the following:

 

1. Interim looks to stop or to adjust patient accrual

2. Interim looks to assess stopping the trial early either for success, futility or harm

3. Reversing the hypothesis of non-inferiority to superiority or vice versa

4. Dropping arms or doses or adjusting doses

5. Modification of the randomization rate to increase the probability that a patient is allocated to the most appropriate arm

 

The logistics of managing traditional, fixed format clinical trials are quite complex. Adapting the design as results arrive, adds to the complexity of design, monitoring, drug supply, data capture and randomization. However, according to PCAST “One approach is to focus studies on specific subsets of patients most likely to benefit, identified based on validated biomarkers. In some cases, using appropriate biomarkers can make it possible to dramatically decrease the sample size required to achieve statistical significance – for example, from 1500 to 50 patients.“ An adaptive trial design enabled two experimental breast cancer drugs to deliver promising results after just six months of testing, far shorter than usual. Researchers assessed the results while the trial was in process and found that 9) ___ had been eradicated in more than half of one group of patients. The trial, known as I-Spy 2, tested 12 experimental drugs. For its predecessor I-SPY 1, 10 cancer centers and the National Cancer Institute (NCI SPORE program and the NCI Cooperative groups) collaborated to identify response indicators that would best predict survival for women with high-risk breast cancer. During 2002-2006, the study monitored 237 patients undergoing neoadjuvant therapy before surgery. Iterative MRI and tissue samples monitored the biology of patients to chemotherapy given in a neoadjuvant setting, or presurgical setting. Evaluating chemotherapy’s direct impact on tumor tissue took much less time than monitoring outcomes in thousands of patients over long time periods. The approach helped to standardize the imaging and tumor sampling processes, and led to miniaturized assays. Key findings included that tumor response was a good predictor of patient survival, and that tumor shrinkage during treatment was a good predictor of long-10) ___ outcome. Importantly, the vast majority of tumors were identified as high risk by molecular signature. However, heterogeneity within this group of women and measuring response within tumor subtypes was more informative than viewing the group as a whole. Within genetic signatures, level of response to treatment appears to be a reasonable predictor of outcome. Additionally, its shared database has furthered the understanding of drug response and generated new targets and agents for subsequent testing. Sources: nih.gov; Wikipedia

 

ANSWERS: 1) devices; 2) benefit; 3) studies; 4) research; 5) effects; 6) dosing; 7) Drug; 8) post-market; 9) cancer; 10) term

 

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