P518 Ulcerative colitis drug development success rates are higher than the industry average

Abstract Background Given the increasing costs of drug development, coupled with low success rates, there is a need to both develop better predictive models and elucidate causes of failure. However, for indications such as ulcerative colitis, a baseline does not presently exist. In this paper, we review trends in drug development and establish a baseline for ulcerative colitis. Methods We used BiomedTracker to obtain information about the number of compounds, which were in development for ulcerative colitis between 2005 and 2018. We counted the number of compounds, which had reached a particular phase, had been discontinued during this phase, had successfully passed it or had been still in this phase. Success rates were derived for the different phases of drug development for all 73 candidate drugs and divided by type of molecule and type of company. A success rate was calculated by dividing the number of drugs successfully completing a particular phase by the sum of the number of drugs which were discontinued during this phase and the number of compounds that completed positively a phase. The likelihood for approval (LOA) for each phase was calculated by multiplying the success rate for the respective phase with the success rates of next stages of development. Results The success rate in phase I was 96 %, in phase II 53 % and in phase III 76%, while the respective LOA was 0.39, 0.4 and 0.76. Table 1 demonstrates the success rates and LOA by type of compound(New molecular entity (NME), Biologic, non-NME) and type of company (big, mid-size, emerging). Conclusion The general industry success rates and LOA for phase I is 64%, for Phase 2 30%, and for phase 3 60% while the LOA from phase I is 10%. These data are published by Michael Hay and co-authors in Nature in January 2014. The success rates in UC drug development are therefore higher than the overall industry success rates.

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Clinical Trial Risk in Type-2 Diabetes: Importance of Patient History

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j3hg73 ◽

2014 ◽

Vol 17 (3) ◽

pp. 393 ◽

Cited By ~ 2

Author(s):

Emmanuel O. Aiyere ◽

Jay Silverberg ◽

Safina Ali ◽

Jayson L. Parker

Keyword(s):

Type 2 Diabetes ◽

Clinical Trial ◽

Phase I ◽

Success Rate ◽

Phase Iii ◽

Success Rates ◽

Glucose Levels ◽

Treatment Naïve ◽

Diabetes Drug

Purpose. To determine the risk of clinical trial failure for drugs developed for type-2 diabetes. Methods. Drugs were investigated by reviewing phase I to phase III studies that were conducted between 1998 and February 2013. The clinical trial success rates were calculated and compared to the industry standard. The drugs were classified into GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitors and “Other”. The exclusion criteria for drugs in this study: Drugs that were started in phase I studies prior to January 1998 for this indication and drugs whose primary indications were not for the control of blood glucose levels. Results. Data was extracted from clinicaltrials.gov; there were a total of 131 drug candidates that fit our specified criteria, of which 8 received FDA approval. The cumulative success rate for molecules developed for type-2 diabetes is 10%. Small molecules were more successful than biologics. A strong disparity was observed in phase III, with studies that utilised treatment naïve patients having a 40% success rate, compared to an 83% success rate in patients who have had previous anti-hyperglycemic exposure. Conclusions. 1 in 10 drugs that enter clinical testing in this disease will be approved. The DPP-4 inhibitor class of drugs had the highest success rate of all drug classes with a 63% cumulative success rate; while treatment naïve patients carried the greatest clinical trial risk. Keywords: Clinical trials, Type-2 diabetes, Drug development, Clinical trial risk. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Parkinson’s Disease Drug Development Since 1999: A Story of Repurposing and Relative Success

Journal of Parkinson s Disease ◽

10.3233/jpd-202184 ◽

2021 ◽

pp. 1-9

Author(s):

Deirdre M. Boucherie ◽

Gonçalo S. Duarte ◽

Tiago Machado ◽

Patrícia R. Faustino ◽

Cristina Sampaio ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Drug Development ◽

Success Rate ◽

Phase 1 ◽

Phase 2 ◽

Development Programs ◽

Inclusion Criteria ◽

Phase 3 ◽

Heterogeneous Nature

Background: A global overview of drug development programs in Parkinson’s disease over the last few decades is lacking, while such programs are challenging given the multifaceted and heterogeneous nature of the disease. Objective: To indirectly assess drug development programs in Parkinson’s disease, exploring some factors associated with compound attrition at different trial phases. Methods: We assessed all Parkinson’s disease trials in the WHO trials portal, from inception (1999) to September 2019. Independent authors selected trials and extracted data. The success rate was the number of compounds that progressed to the next drug development phase divided by the number of compounds in that phase. Results: Overall, 357 trials (studying 152 compounds) fulfilled our inclusion criteria, with 62 (17.3%) phase 1 trials, 135 (37.8%) phase 2 trials, 85 (23.8%) phase 3 trials, and 53 (14.8%) phase 4 trials. The success rate was 42.4% from phase 2 to 3. Original compounds received regulatory approval by the FDA in 21.4% of cases, compared with 6.7% of repurposed compounds, representing an overall success rate of 14.9%. We found 172 trials (48.2%) conducted for repurposing previously licensed compounds. These figures were approximately the same regarding approval by the EMA. Most compounds were approved to treat parkinsonism and motor fluctuations. Conclusion: We found a moderate-to-high success rate in all phases of drug development. This was largely based on the success of original compounds, despite almost half of the identified trials attempting compound repurposing.

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Clinical trial risk reduction in non-small cell lung cancer though the use of biomarkers and receptor-targeted therapies.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.8040 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 8040-8040

Author(s):

Adam Falconi ◽

Gilberto Lopes ◽

Jayson L. Parker

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Drug Development ◽

Phase I ◽

Success Rate ◽

Targeted Therapies ◽

Phase Iii ◽

Clinical Testing ◽

Phase Ii Trials ◽

Phase Iii Trials

8040 Background: We analyzed the risk of clinical trial failure duringnon-small cell lung cancer (NSCLC) drug development between 1998 and 2012. Methods: NSCLC drug development was investigated using trial disclosures from publically available resources. Compounds were excluded from the analysis if they began phase I clinical testing before 1998 and if they did not use treatment relevant endpoints. Analysis was conducted in regards to treatment indication, compound classification and mechanism of action. Costs of clinical drug development for advanced NSCLC were calculated using industry data and assumptions, a 9% yearly discount rate and assuming a clinical trial length of 2.5 years for phase I trials, 4 years for phase II trials, 5 years for phase III trials and an average of 5 phase I trials, 7 phase II trials, and 4 phase III trials per approved drug. All funding costs are in US dollars (USD). Results: 2,407 clinical trials met search criteria. 676 trials and 199 unique compounds met our inclusion criteria. The likelihood, or cumulative clinical trial success rate, that a new drug would pass all phases of clinical testing and be approved was found to be 11%, which is less than the expected industry aggregate rates (16.5%). The success of phase III trials was found to be the biggest obstacle for drug approval with a success rate of only 28%. Biomarker-guided targeted therapies (with a success rate of 62%) and receptor targeted therapies (with a success rate of 31%) were found to have the highest likelihood of success in clinical trials. The risk-adjusted cost for NSCLC clinical drug development was calculated to be 1.89 billion US dollars. Use of biomarkers decreased drug development cost by 26% to 1.4 billion US dollars. Potential savings may be even higher if fewer clinical trials are required for successful development. Conclusions: Physicians that enroll patients in NSCLC trials should prioritize their participation in clinical trial programs that involve either a biomarker or receptor targeted therapy, which appear to carry the best chances for a successful treatment response. Given the high adjusted cost of clinical testing alone in NSCLC, efforts to mitigate the risk of trial failure need to explore these factors more fully.

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Risk of Failure of a Clinical Drug Trial in Patients with Moderate to Severe Rheumatoid Arthritis

The Journal of Rheumatology ◽

10.3899/jrheum.120005 ◽

2012 ◽

Vol 39 (11) ◽

pp. 2066-2070 ◽

Cited By ~ 11

Author(s):

KAVISHA S. JAYASUNDARA ◽

EDWARD C. KEYSTONE ◽

JAYSON L. PARKER

Keyword(s):

Rheumatoid Arthritis ◽

Clinical Trial ◽

Phase I ◽

Success Rate ◽

Phase Iii ◽

Severe Rheumatoid Arthritis ◽

Success Rates ◽

Industry Standard ◽

Industry Standards ◽

Approved Drugs

Objective.We conducted a systematic review to determine the risk of drug failure in clinical testing with patients with moderate to severe rheumatoid arthritis (RA).Methods.Therapies for RA were investigated by reviewing phase I to phase III studies conducted from December 1998 to March 2011. Clinical trial success rates were calculated and compared to industry standards. Trial failures were classified as either commercial or clinical failures. The exclusion criteria for drugs in this study: drugs that were started in phase I studies prior to January 1998 for this indication; or studies that enrolled patients who were methotrexate-naive and/or had failed biologic therapy.Results.A search in clinicaltrials.gov and approved drugs for the indication yielded a total of 69 drugs that met the study criteria. The cumulative success rate was determined to be 16%, which is equivalent to the industry standard of 16%. For each phase, the frequency of clinical failures exceeded commercial failures. Clinical studies equally comprised investigations of small molecules and biological agents, but biologics seemed to exhibit a higher success rate overall.Conclusion.Clinical trial risk in RA with the 84% failure rate reported here is at par with industry performance and phase II success rate seems to be highly predictive of phase III success.

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Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

Advances in Pulmonary Hypertension ◽

10.21693/1933-088x-9.4.214 ◽

2010 ◽

Vol 9 (4) ◽

pp. 214-219

Author(s):

Robyn J. Barst

Keyword(s):

Clinical Trials ◽

Pulmonary Arterial Hypertension ◽

Drug Development ◽

Phase 1 ◽

Preclinical Studies ◽

Phase 2 ◽

Phase 3 ◽

Preclinical Testing ◽

New Drug ◽

Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

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Impact of PSMA PET/CT on SRT planning: Preliminary results from the randomized phase III trial NCT03582774.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.30 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 30-30

Author(s):

Jeremie Calais ◽

Wesley R Armstrong ◽

Amar Upadhyaya Kishan ◽

Kiara M Booker ◽

David Elashoff ◽

...

Keyword(s):

Success Rate ◽

Phase Iii ◽

Open Label ◽

Phase 3 ◽

Preliminary Results ◽

Volume Delineation ◽

Psma Pet ◽

Pet Ct ◽

The Impact

30 Background: The purpose of this trial is to evaluate the success rate of salvage radiation therapy (SRT) for recurrence of prostate cancer (PCa) after radical prostatectomy with and without planning based on prostate specific membrane antigen (PSMA) positron emission tomography (PET). Methods: This is a multicenter, prospective, randomized, controlled, open-label, Phase 3 clinical imaging trial powered for clinical outcome at 5 years. UCLA is the leading central site in which PSMA PET, clinical follow-up and data management are being done. UCSF was a participating site in which PSMA PET imaging can be done. SRT can be performed anywhere, patients are followed remotely by the UCLA investigators. Patients scheduled for SRT for recurrence after primary prostatectomy and with PSA ≥ 0.1ng/ml at time of enrollment were eligible. Patients were randomized to proceed with standard SRT allowing for any conventional imaging aside from PSMA PET/CT (control arm) or undergo a 68Ga-PSMA-11 PET/CT scan prior to SRT planning (investigational arm). The primary endpoint is the success rate of SRT at 5 years in patients who undergo SRT. We report here the preliminary results of a secondary endpoint: the impact of PSMA PET on SRT planning by comparing the pre-randomization RT plans prospectively obtained on surveys before randomization to the actually delivered RT plans obtained after follow-up. Results: Enrollment of the trial was complete. 193 patients were enrolled from 09.06.2018 to 08.17.2020. 7/90 patients (9%) in the control arm dropped-out the study because they underwent a PSMA PET at another institution, while 1/103 (1%) patients of the intervention arm dropped-out due to COVID-19 related complications. After a median follow-up of 13.3 months (last follow-up date 09/01/2020), delivered RT plans were obtained in 60/83 (72%) and 70/102 (69%) of patients of the control and the PSMA arms, respectively. Median PSA at enrollment was 0.32 ng/ml (IQR 0.17-1.35) and 0.22 ng/ml (IQR 0.14-0.50) in the control and PSMA arms, respectively. There was a change between the intended pre-randomization RT plan and the actually delivered RT plan in 17/60 (28%) and 40/70 (57%) of the patients in the control and PSMA arms, respectively (p = 0.002). SRT was aborted in favor of systemic therapy and/or metastasis directed RT for extra-pelvic M1 disease in 2/60 (3%) and 12/70 (17%) of the control and PSMA arms, respectively (p = 0.17). Dose prescription and/or target volume delineation was changed in 2/60 (3%) and 1/70 (26%) in the control and PSMA arms, respectively (p = 0.001). Conclusions: In this prospective randomized phase 3 study, PSMA PET had an impact on the SRT plan in more than half of the patients. Long-term follow-up will show if the impact of PSMA PET on SRT planning translates into improved outcome or not. Clinical trial information: NCT03582774.

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P463 Induction of endoscopic response: a network meta-analysis of induction studies comparing ontamalimab with other treatments for moderate-to-severe ulcerative colitis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.592 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S410-S411

Author(s):

A Vickers ◽

A Nag ◽

B Devine ◽

B E Sands ◽

R Panaccione ◽

...

Keyword(s):

Ulcerative Colitis ◽

Large Scale ◽

Meta Analysis ◽

Placebo Response ◽

Study Data ◽

Induction Treatment ◽

Phase 2 ◽

Odds Ratios ◽

Phase 3 ◽

Random Effects Models

Abstract Background Clinicians, patients, payers and policymakers require relevant, high-quality evidence to support decision-making regarding the treatment of ulcerative colitis (UC). In the absence of head-to-head trials, network meta-analysis (NMA) can be used to compare treatments. We conducted an NMA to compare the efficacy of ontamalimab (anti-MAdCAM-1) using its phase 2 data, with all biologics and novel small molecules for which induction study data on endoscopic response were available. Methods A systematic literature review was conducted in November 2017 to identify published randomised controlled trials of induction treatment in patients with moderate-to-severe UC. An NMA of the identified studies was performed using random-effects models and methods based on NICE guidance. Odds ratios and 95% credible intervals were calculated to describe the relative differences between treatments and placebo in terms of efficacy in inducing endoscopic response. Results were examined by anti-TNF status (naïve vs. experienced). Results In total, 15 phase 2 and phase 3 induction studies of the following agents were available and included: adalimumab (160/80mg), etrolizumab (100mg and 300mg), golimumab (200/100mg), infliximab (5mg), ontamalimab (22.5mg and 75mg), ozanimod (0.5mg and 1mg), tofacitinib (10mg) and vedolizumab (300mg). The definition of endoscopic response (improvement) in all trials was a Mayo endoscopic subscore of ≤1. Homogeneity between studies was good, enabling pooling of results. Figure 1 shows odds ratios for induction of endoscopic response with treatments relative to placebo in anti-TNF-naïve and -experienced patients. All treatments performed significantly better than placebo in anti-TNF-naïve patients, with the exception of both doses of etrolizumab and ozanimod 0.5 mg. Significant differences between some treatments were observed; specifically, ontamalimab 22.5 mg (p = 0.0277), tofacitinib 10 mg (p = 0.0233) and infliximab 5 mg (p = 0.0047) were all superior to adalimumab 160/80 mg. Conclusion This study suggests that ontamalimab, infliximab and tofacitinib could be superior to adalimumab in inducing endoscopic healing, although it was conducted before any large-scale head-to-head trials of these drugs. Furthermore, large variances due to differing endpoint timings, the combination of phase 2 and phase 3 data, and lack of control for placebo response rates preclude firm conclusions being drawn.

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The transition from phase II to phase III studies

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.6514 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 6514-6514 ◽

Cited By ~ 2

Author(s):

I. Tannock ◽

A. Gulamhusein ◽

D. R. Berthold

Keyword(s):

Phase Ii ◽

Phase Iii ◽

Phase 2 ◽

Phase Ii Trials ◽

Phase 3 ◽

Phase 2 Trial ◽

Time Period ◽

Phase 2 Study ◽

New Treatment ◽

Background Phase

6514 Background: Phase II trials are performed to detect potential anti-tumor effects of a new treatment and should be used to decide whether to proceed to a phase 3 trial or not. However, many phase 2 trials never lead to a phase 3 trial despite encouraging results. Here we sought to determine how often (i) positive phase 2 trials have led to phase 3 trials, and (ii) how often phase 2 trials were designed to lead to a phase 3 trial. Methods: We reviewed 200 phase 2 trials, presented at ASCO meetings in 1995–1996, and 2006, selecting randomly 20 abstracts with encouraging results for 5 cancer sites (breast, lung, GI, GU, Gyn) in each time period. For those presented in 1995–1996, we searched systematically for subsequent randomized studies where one treatment arm was similar to that in the phase 2 study. For those presented in 2006, a questionnaire was sent to authors asking whether they recommend evaluating the regimen in a phase 3 trial, whether a phase 3 trial is planned and whether resources (budget, patients, drugs) are available to conduct a phase 3 trial. Results: Ten years after presenting phase 2 trials with positive results, only 13 regimens have been evaluated in a phase 3 trial. Of 100 investigators who presented a phase 2 trial in 2006, 42 returned the questionnaire, 36 confirmed that the results met criteria of efficacy and 25 thought the regimen should be evaluated in a phase 3 trial. Only 10 investigators plan to undertake a phase 3 trial, and 8 stated they had resources to do so. Reasons for not planning a phase 3 study included insufficient efficacy (7), insufficient access to patients (5) or financial support (5), lack of interest from colleagues (6), and lack of support from the company (8). Conclusions: Few (∼13%) phase 2 trials with promising activity are followed by phase 3 trials and this is not increasing with time. Reasons include lack of resources such as money, drugs and patients. Many of these limitations are known when planning the phase 2 study, implying that many phase 2 trials are not planned as precursors of phase 3 trials. Resources spent on such trials would be better applied to practice-changing phase 3 trials. No significant financial relationships to disclose.

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Inefficiencies in the phase II to phase III transition as a modifiable factor that is impeding successful drug development for glioblastoma.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.2516 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 2516-2516

Author(s):

Adithya Balasubramanian ◽

Ashray Gunjur ◽

Umbreen Hafeez ◽

Sid Menon ◽

Lawrence Cher ◽

...

Keyword(s):

Drug Development ◽

Primary Endpoint ◽

Pearson Correlation ◽

Phase Iii ◽

Design Parameters ◽

Trial Participation ◽

Phase 2 ◽

Medline Search ◽

Mesh Terms ◽

The Impact

2516 Background: Improving the outcomes of patients with glioblastoma (GBM) represents one of the most significant challenges in neuro-oncology. We have observed inefficiencies in the availability and use of phase 2 data when planning phase 3 studies, and have undertaken a detailed review of key design parameters of phase 2 and 3 trials in GBM to identify and quantify the impact of this phenomenon. Methods: Studies between 2005-2019 inclusive were identified though MEDLINE search using keywords and MeSH terms, and manual bibliography searches. P2Ts were restricted to those referenced by the corresponding P3Ts. Clinical, statistical and sponsor characteristics were extracted by two reviewers (AB&AG). For each P3T, corresponding Phase 2 trial (P2T) data was “optimally matched” (OM) where same drug was used in similar schedule and similar GBM population; “partially matched” (PM) where dis-similar schedule and/or treatment setting; and “lacking” in all other circumstances. The statistical data used in the P2/3 transition were compared by Pearson Correlation, Fisher’s Exact or Chi-square testing as appropriate. Results: Of 20 P3Ts identified, 6 (30%) lacked any phase 2 data. Of the remaining 14 P3T, 9 had 1 prior P2T, 4 had 2 P2T and 1 had 3 P2T, for a total of 20 P3T-P2T pairs (called dyads). Further, there were 13 OM dyads and 7 PM dyads. OM dyads showed strong concordance for mPFS (r2= 0.95, p < 0.01) and mOS (r2= 0.84, p < 0.01), whilst PM dyads did not (p > 0.05). We identified several inefficiencies in translation from P2T to P3T. Firstly, 3 P3T had statistical assumptions of primary endpoint that may have been too optimistic. 2 of these P3Ts aimed for an expected endpoint that was higher than the actual outcomes from a matched P2T. 1 P3T was unable to reach the desired sample size. We note that 4 P3Ts had actual primary endpoint HRs that were < 0.9 but with P > 0.05. Finally, we investigated whether there were absolute thresholds for efficacy in P2Ts to inform whether to proceed with P3Ts. For P2Ts in the newly diagnosed setting, all those with mPFS < 14 months and/or mOS < 22 months had subsequent negative P3Ts. For P2Ts in recurrent disease, all those with mPFS < 6 months and mOS < 12 months had negative P3Ts. Applying these thresholds to the studies in our review, 10 of the 12 negative P3Ts (83%) with matched P2Ts need not have been initiated, sparing 4739 patients’ from unnecessary trial participation. Conclusions: Our data strongly supports the vital role of properly designed P2Ts in informing P3Ts for drug development for primary CNS tumours.

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