published_or_final_version / Community Medicine / Master / Master of Public Health

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No description available.

The World Health Organization estimates that 4 billion people use herbal medicine for some aspect of primary health care. These herbal products are however mostly used without the necessary clinical trial done to prove their pharmacological activities and, therefore, their quality, efficacy and safety. It was the objective of this study to review the current international guidelines for the evaluation of herbal medicine / to gain a perspective on the number, type and quality of clinical trials that have been done on herbal medicine and to adopt a set of guidelines that could be used to conduct trial on a traditional herbal medicine used in South Africa. To verify these guidelines, a protocol for a clinical trial was drafted and submitted for approval to the regulatory and ethical authorities in South Africa.

Background Surrogate outcomes are measures of treatment effect that can be used to predict treatment effect on the true outcome of interest. Surrogates are valued as they can be used in place of true outcomes to reduce the length, size, or intrusiveness of a clinical trial. However, validation of surrogacy is a conceptually complicated area and much theoretical and practical statistical development has been conducted in recent years. Methods A systematic review was conducted to identify which surrogate evaluation approach was best suited to be extended to ordinal outcomes. I extended a foremost approach to the case where the surrogate, the true clinical outcome, or both are ordinal outcomes. This extension investigated surrogacy at both the trial and individual levels; trial level surrogacy was based on a two stage method. The extension was developed through large simulation studies and used to investigate whether deep venous thromboembolism (DVT) was a surrogate for the ongoing measure of death and disability the Oxford Handicap Scale (OHS), using data from the stroke trial CLOTS3. CLOTS3 was a large multi-centre randomised clinical trial which investigated whether intermittent pneumatic compression (IPC) applied to the legs reduced the occurrence of deep venous thromboembolism (DVT) in stroke clinical trial patients. Results The systematic review identified the information theory approach as the most intuitively and practically worthwhile approach to surrogacy evaluation. I extended this approach to: a binary surrogate and ordinal true outcome (the binary-ordinal setting); the ordinal-binary and the ordinal-ordinal settings. The simulation studies showed that the approach worked well in most scenarios tested. However, trial level surrogacy was impacted by loss of efficiency due to the use of the two stage method. Bias imposed at the trial level by separation of discrete outcomes was effectively dealt with using a penalised likelihood method. The information theory approach for ordinal outcomes identified no surrogate that would predict treatment effect of IPC on the true outcome OHS measured at six months in the stroke trial CLOTS3.

The pharmaceutical industry is currently facing an industry wide problem of high attrition rates for new compounds and rising development costs. As a result of this, there is an emphasis on making the development process more ecient. By learning more about new compounds in the early stages of development, the aim is to stop ineective compounds earlier and improve dose selection for compounds that progress to phase III. One approach to this is to use adaptive designs. The focus of this thesis is on response adaptive designs within phase IIb dose-finding studies. We explore adapting the subject allocations based on accrued data, with the intention of focusing the allocation on the interesting parts of the curve and/or the best dose for phase III. In this thesis we have used simulation studies to assess the operational characteristics of a number of response adaptive designs. We found that there were consistent gains to be made by adapting when we were relatively cautious in our method of adaptation. That is, the adaptive method has the opportunity to alter the subject allocation when there is a clear signal in the data, but maintains roughly equal allocation when there is a lot of variability in the data. When we used adaptive designs that were geared to randomising subjects to a few doses, the results were more varied. In some cases the adaptation led to gains in efficacy whilst in others it was detrimental. One of the key aims of a phase IIb dose-finding study is to identify a dose to take forward into phase III. In the final chapter, we show that the way in which we choose the dose for phase III affects the expected gain, and so begin to consider how we can optimise the decision making process.

Class of 2007 Abstract / Objectives: In this paper we analyzed the time frame for oncology drugs that were designated as a fast track drug and the time transition from a phase II to phase III clinical trial completion. Methods In our study we utilized oncology drugs that were approved between the years of 2000-2006 (FDA.gov). We then analyzed the CDER data base that provided information to Fast Track drugs that have been approved within the time period as determined by the FDA selection criteria (21 CFR 312.81(a)). Under certain circumstances, the FCA may consider reviewing portions of a marketing application in advance of the complete New Drug Application (NDA) or Biologic License Application (BLA). We will evaluate fast track designated products which may also be eligible to participate in FDA’s Continuous Marketing Applications Pilot 1 or Pilot 2 programs. For our analysis, we specifically selected oncology drugs. In particular, we analyzed 32 drugs from the stated time period. Each fast track drug was then selected and analyzed for its clinical phase development time period based on news announcements during clinical trails. For each announcement we conducted an event study analysis through lexis Nexus with respect to the announcement of a clinical trial enrollment, clinical trials news (Phase I, II, III). Results: The results of our preliminary study show that there was a shorter time to development transition for the fast track oncology drugs. The oncology clinical phase transition from II to three on average lasted 12 months with a range of 2 - 29 months The average length of the phase development had to excludes 4 drugs due to the lack of information provided from the LexisNexis database. The current timeline for fats track drugs has shown a decrease in transition from clinical trials to the market. In the example of Spyrcel, the data from our study had to be excluded, there was a definitive difference in the time to approval process for the drug as compared to other standard review entities. The approvals for dasatinib, or Sprycel, for refractory CML was shown to move through the development to approval in one of the fastest timeframes in modern development. Since its first clinical study on in Gleevec-resistant patients, the medication was decided on entering an accelerated timeline. It took us just 25 months to bring Sprycel from first-in-human dosing to a regulatory submission. In contrast, the industry average for this cycle time is 6.4 years which is three times greater than the cycle time for Sprycel. Conclusions: The new Subpart H regulations state that post-marketing studies to confirm clinical benefit that would consist usually by "studies underway” at the time of accelerated approval, this has not always been the case and is not a requirement (Dagher R, Johnson J, Williams G et al). In conclusion, the accelerated approval program in oncology has been successful in making 18 different products available to patients for 22 different cancer treatment indications since the inception of the fast track program. From the current data and transition information, there is a comparative difference between the clinical phase transitions from phase II to Phase III clinical trials. However, this preliminary data needs to be further evaluated against the standard FDA review process from oncology drugs. Moreover, further studies will be needed to interpret whether the average length of oncology studies biases the value of our study.

Thesis (M. Med. Sc.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 47-55).

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (p. 158-160).