Overview of Drug Development
Mark Chang, John Balser, Jim Roach, Robin Bliss in Innovative Strategies, Statistical Solutions and Simulations for Modern Clinical Trials, 2019
Clinical Development traditionally includes phase I to Phase IV clinical trials. Clinical trials are experiments of the test drug conducted on human subjects in accordance with Good Clinical Practice (GCP) guidances and regulations. Phase I trials are usually conducted on a small group healthy volunteers. The objectives of a phase I trial are typically to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of a drug in humans. Successful Phase I trials will lead to a further test of the NCE in a Phase II trial with an increased sample-size to further define the safety profile, preliminary efficacy, and optimal dose range, and to mitigate risks of investing an ineffective NCE in a large scale. If the Phase II results show the test drug is safe and efficacious enough to warrant for further study. Phase III trials are launched with the objective of providing definitive trial data regarding the safety and efficacy for the target indication. The size of the populations in the trials or sample-size should be sufficiently large so that there are adequate probabilities (power) to demonstrate statistical significance if the test drug in fact is effective. Successful Phase III trials lead ultimately to approval and commercialization of the drug. However, a Phase IV trial may sometimes be be conducted as a requirement for the conditional regulatory approval.
Clinical Trials
Michael Ljungberg in Handbook of Nuclear Medicine and Molecular Imaging for Physicists, 2022
If a relevant level of efficacy is found in phase II, and no special toxicity concerns have been identified, the drug is ready for phase III – that is, a randomized trial comparing the new drug to placebo or standard treatment for the indication pursued. The gold standard for phase III trials is a randomized, double-blind, placebo-controlled and multicentre trial. Randomization means that the subjects are randomly assigned either to the experimental arm or to the standard/placebo arm. Double-blind means that neither the investigator/doctor nor the subject knows whether he or she is receiving the investigational drug or placebo/standard treatment. Placebo is an inactive substance that has been prepared in the same format as the investigational drug, and in such a way that it is impossible to know whether it contains the active substance or not. To include several centres in a trial is a way to minimize bias in patient selection, patient management, and so forth, that may otherwise differ between different sites/hospitals/countries in a way that may affect outcomes. The number of subjects required to prove a difference between the control arm and the experimental arm depends on how large the difference is between the two – the larger the difference the smaller the sample size required to prove it. Phase III trials generally include hundreds or even thousands of subjects.
P
Filomena Pereira-Maxwell in Medical Statistics, 2018
A clinical trial that is conducted to evaluate the efficacy of new (or existing) drugs against standard treatments or placebos, or the effectiveness of the same once their safety and efficacy have been provisionally established. Phase III trials are normally conducted in the typical settings where patients and clinicians interface. Efficacy or explanatory trials are conducted under a stricter protocol than effectiveness trials, including more restrictive eligibility criteria. The latter require a larger number of patients, in order to account for protocol breaches and greater between-patient variability of response, and to allow small treatment effects to be detected when evaluating treatments for common diseases. In the latter situation, while the treatment effects may be modest the net impact may nonetheless be considerable. See superiority trial, equivalence trial and non-inferiority trial; crossover design, parallel design and factorial design for types of study and study designs for Phase III trials. See also explanatory trial, perprotocol analysis, pragmatic trial, intention-to-treat analysis, Phase II trial, Phase IV study; POCOCK (1983), MACHIN & CAMPBELL (2005), Sackett, in HAYNES et al. (eds., 2006), and SENN (2008).
Serious dermatological adverse effects of vortioxetine: two cases
Published in Psychiatry and Clinical Psychopharmacology, 2018
Phase IV: Once a candidate compound has successfully completed two adequate and well-controlled studies, a new drug application can be prepared and submitted to the appropriate regulatory body. Objective of postmarketing surveillance studies include the identification of low-frequency adverse events, continued safety monitoring to better characterize known risks, gauging the potential for drug–drug interactions, establishing treatment guidelines for pediatric and geriatric populations, and determining the real-world efficacy of the candidate compound. Side effects that do not occur during the clinical trials can be reported during this phase. Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in clinical practice and should not be compared to the rates in the clinical trials of another psychotropic drug. The drug development process lasts for the entire patent lifetime. Studies conducted for use in new indications after drug use has been accepted as Phase III trials and are performed in accordance with the same rules. The development of new doses and formulations should also be examined afterwards. In the pharmaceutical industry, when brand-name companies patent new inventions that might be in fact just slight modifications of old drugs, it is called “evergreening.”
The modern role of antipsychotics for the treatment of agitation and psychosis in Alzheimer’s disease
Published in Expert Review of Neurotherapeutics, 2018
Byron Creese, Miguel Vasconcelos Da Silva, Iskandar Johar, Clive Ballard
Among the emerging non-antipsychotic agents, dextromethorphan-quinidine (AVP-786) is a particularly attractive alternative to antipsychotics due to its known safety profile, resulting from its existing license for pseudobulbar affect. A major phase II 10-week RCT has shown evidence of a statistically significant but modest improvement in agitation and aggression among those randomized to treatment (reduction in NPI agitation/aggression from 7.1 to 3.8 compared with 7 to 5.3 in the placebo group). Moreover, at each stage of the study, the response favored the treatment arm [60]. The mechanism of action of dextromethorphan is relevant to agitation in AD, notably inhibition of serotonin and norepinephrine reuptake. It also has analgesic properties, which are consistent with the findings described earlier suggesting analgesia as an effective therapy for agitation [50]. Adverse events included falls, urinary tract infections (UTI), and diarrhea but not cognitive decline, sedation, or clinically meaningful QTc prolongation. The increased rate of falls, although not statistically significant, is of concern and it is premature to draw concrete positive conclusions around safety as this was a relatively small study (N = 220) and safety is difficult to comprehensively assess over a 10-week period. Longer studies are needed to conclusively demonstrate safety. Phase III trials are now underway in much larger samples over a 12-week period, with completion due in 2019 and importantly, there will also be an extension study examining safety over a period of 56 weeks in 700 people.
A comparison of human natural monoclonal antibodies and aptamer conjugates for promotion of CNS remyelination: where are we now and what comes next?
Published in Expert Opinion on Biological Therapy, 2018
Maria K. Perwein, John A. Smestad, Arthur E. Warrington, Robin M. Heider, Mark W. Kaczor, Louis J. Maher, Bharath Wootla, Ahmad Kunbaz, Moses Rodriguez
One important aspect is how efficacy will be measured in patients as to their effect on promoting remyelination either by aptamers or antibodies. Phase I trials will be focused on treating patients with gradually increasing dosage of antibody or aptamer to determine possible toxicity. This has already been performed in the Phase I trials with rHIgM22. Phase II trials will be focused on determining clinically significant endpoints based on the clinical deficits of the patients. Therefore if the patient is presenting with optic neuritis then visual acuity, color vision, visual evoked responses, visual fields will be used as relevant endpoints. If the patient presents with motor deficits then increase in motor power, improved gait speed in a 25 foot gait analysis, 9 peg hole test in a patient with upper motor strength will be used. In patients with sensory deficits, a somatosensory evoked response test can be a non-biased approach to showing improvement since clinical sensory testing in patients may have bias. In all of these situations, patients with acute attacks not responding to conventional intravenous steroids will be first tested to see if the aptamer or antibodies improve function. If there is an effect on patients with acute attacks, then the aptamer or antibodies may be tried on patients with progressive deficits. The endpoints in these situations will likely be at 2 or 3 years following therapy. The issue of proving remyelination will be dependent on showing changes by newer methods of MRI, such as MTR and diffusion tensor imaging. The Phase III trials will be dependent on the findings in the Phase II trials.
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