What constitutes a successful clinical trial?

2. january 2016 at 19:08 | Veronika Valdova, ARETE-ZOE |  Medicine & Pharmacy

NHLBI has issued the first in a series of Requests for Information (RFIs) to solicit input from its stakeholders on ways to optimize the clinical trials enterprise:

"Characteristics of a successful clinical trial (recognizing that a clinical trial can be assessed in a variety of ways, including but not limited to advancing science and completing a trial on time and on budget)"

Risks to project success often result from a sequence of logically dependent decisions and actions by independent entities that operate within a clinical trial. Any incorrect assumptions made earlier in the process of drug discovery and pre-clinical development about drug characteristics and mode of action, which cannot be independently verified or remain concealed or unrealized through subsequent development phases can contribute to a patient casualty.[1]

Information on products is heavily dependent on clinical studies generated by the industry or funded by the industry. Non-registered studies, unpublished studies, and delays in registration of studies create an important disconnect between produced results and perceived findings. Registration of clinical studies improved the situation considerably over the last 15 years but did not resolve the selective information flow from the industry to medical professionals (publication bias and multiple publication bias). Multiple publication of a positive study amplifies such information, creating a false positive incentive for prescription (widely publicized anecdotal finding) whilst suppression of negative studies (publication bias) limits access to potentially crucial information for healthcare professionals.[2]

Very varied design of clinical studies makes them difficult to interpret by the target audience (regulators and healthcare professionals). Industry can opt for wide variety of designs to prove value of the product. Uncertainty about risks plays in favor of the producer especially after the drug has reached the market. Intentional avoidance of the producer to design and conduct studies empowered to define risks to patients, and disclose and mitigate these risks accordingly, can be interpreted as intentional interaction with uncertainty.[3]

Redefinition of trial success vs. failure would profoundly affect the value of trial results to other stakeholders, i.e. clinicians, investors, payers, and patients.

Independent assessment of "value" of a clinical trial would enable researches, medical professionals, investors and payers to make valid and reliable assessments of large numbers of differently designed trials. Rigorous assessment of "value" of a trial would also provide incentive to trial sponsors to prioritize resources toward trials, which provide clinically meaningful information, and improve their overall metrics. Trials without posted results have no meaning and no value for the consumer.
  • Are questions posed by the trial clinically relevant? The use of surrogate endpoints in trials should always be compared against real life data (EHR) and true clinical outcomes.
  • Does the trial answer the questions posed with high internal validity[4] and construct validity[5]?
  • Does the trial have statistical power[6] to answer research questions posed with high validity and confidence? Unsuccessful clinical trial does not have the statistical power to answer conclusively research questions.
  • High confidence in cause and effect relationship is essential for truthful communication with investors and validity of any assumptions made in the future based on the results of such trial.
  • Uncertainty of the meaning of data coming from clinical trials, its validity, accuracy, and confidence, which can be placed on each study, may be resolved through standardization of design of certain types of clinical studies through implementation of ISO standards. ISO standardization could reduce many uncertainties and increase probability of detection of reasonably foreseeable risks for individual therapeutic areas.
  • Incentives toward timely and complete publication of trial results (ClinicalTrials.gov).
  • Incentives to include NCT number in all publications as a clear identifier of data source.
  • Discouragement of multiple publication of the same trial in multiple different journals.
[1] Valdova V, Sheckler R, Abdulkhaleq A, Wagner S: The usability of Systems-Theoretic Accident Model and Processing (STAMP) in drug development (manuscript, 2015).
[2] Valdova V, Sheckler R: Risk Analysis Primer. http://www.aretezoe.com/#!risk-analysis-primer/c1h0v (Dec 2014)
[3] Ibid.
[4] Internal validity is the confidence that we can place in the cause and effect relationship in a study: "Could there be an alternative cause, or causes, that explain my observations and results?"
[5] Construct validity determines whether the program measured the intended attribute.
[6] The power of a statistical test is the probability that the test will reject the null hypothesis when the null hypothesis is false i.e. it will not make a Type II error, or a false negative decision. As the power increases, the chances of making a Type II error decrease. The probability of a Type II error is referred to as the false negative (β). Therefore power is equal to 1‐β, which is also known as the sensitivity.

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