Using the target product profile write the following strategies and justify the strategy adopted
Updated: May 25, 2021
An assignment by: Darren Wogman MSc. Completed as part of Pharmaceutical Medicine MSc at King's College London
a. A preclinical strategy to enable the marketing of the drug in the selected indication
The preclinical work required to support the marking application for ATL-104 has been outlined in the TPP produced as part of Assignment 1. This has been reproduced below:
“6-month repeat-dose toxicity in Sprague-Dawley rats 9-month repeat-dose toxicity in Beagle dogs Immunogenicity assessment 104-week carcinogenicity study in Sprague-Dawley rats 26-week carcinogenicity study in transgenic mouse 23-week reproductive toxicology study in Sprague–Dawley Rats (Wolfe, 2010)” (Wogman, D. 2019).
b. A phase 3 clinical trial design. This trial design needs to include and justify
1. The overall design of the trial in terms of group recruitment 2. An expected sample size and justification 3. The endpoints required for the trial in terms of both the regulatory requirements and commercialisation strategy Protocol Number
Title of Study
A.ROMP – ATL-104 Reducing Oral Mucositis Prevalence. A Phase III, Placebo-Controlled, Double-blind, Randomised study in patients diagnosed with HPV-related Head and Neck cancer.
Phase of Clinical Trial
King’s College London
To be administered as first-line treatment to HPV-related Head and neck cancer (HNC) patients suffering with Oral Mucositis (OM).
Demonstrate a reduction of maximum severity and duration of OM as per, WHO and WCCNR scales.
Demonstrate a reduction in the number of additionally required hospitalisations related to OM.
Demonstration of efficacy in other sub-populations of HNC patients as per EMA guidelines (EMA.europa.eu, 2019).
This Phase III randomised, double-blind, multicentre study will confirm the efficacy of swillable/swallowable ATL-104 mouthwash product (+standard of care) vs placebo mouthwash (+ standard of care) in HNC patients diagnosed with OM.
Eligible adult patients that have HPV-related HNC, diagnosed with OM or severity >=3 on the WHO scale, and have a treatment plan to receive chemo- or radio-therapy will be enrolled. They will receive either ATL-104 or placebo mouthwash twice daily at the start of each therapy cycle.
248 HPV-related HNC patients will be block randomised in 3:1 ratio in this study as it would be unethical to assign 1:1 ratio for active and placebo groups due to the health status of these patients (Bogaerts et al., 2015). This sample size has been calculated with data from Henke et al., (2011) who found in their palifermin study, the incidence of severe OM in the control group was 69%. A clinical trial looking at palifermin and reduction of OM severity (Clinicaltrials.gov, 2016), determined that 25% decrease was clinically significant. A dichotomous endpoint, 2 independent sample calculation at 80% power provides a total sample size of 160 (α=0.05 and β=0.2). While this would be acceptable, 90% power is preferable as it increases the confidence that the result will be detected (Röhrig et al., 2010), this provides a sample size of 216 (α=0.05 and β=0.1). Henke et al., (2011) also showed a study discontinuation rate of 14%. As such the total sample size required for this study is 248.
While the study is primarily focussed on HPV-related HNC, if sufficient patient numbers can be recruited to also provide indications in other HNC disease areas, they will be included in the study and appropriately stratified during block randomisation to ensure an even proportion of these in each of the two groups.
Participants will be centrally allocated to their treatment group (Active and control) by an independent statistician-approved block randomisation scheme. Participants will be provided their treatment and be subject to assessment as per the protocol design.
The stratification factors for block randomisation will be: Current standard of care, severity of OM as per WHO scale, sex, age, number of cancer treatment cycles already received, Specific sub-group of HNC (i.e. HPV, pharynx, larynx, nasopharynx and hypopharynx).
(1) Randomisation and screening
(3) Post treatment Follow-up
As part of the screening process, all participants must give informed consent in advance of the commencement of any study processes.
Post-treatment assessment consists of a measurement of OM after each chem-/radio- therapy cycle for the rest of the treatment course and a recording of any hospitalisations required as a result of OM.
Patients block randomised into the active group will receive 15ml of ATL-104 mouthwash at 50mg/ml concentration, twice a day for 6 days (+ current standard of care) at the start of each chemo-/radio- therapy cycle.
Patients block randomised to the control group will receive 15ml of saline mouthwash, twice a day for 6 days (+ current standard of care) at the start of each chemo-.radio- therapy cycle.
Patients will continue their treatment until study close or withdrawal. Any study participants that experience clinical benefit as a result of their treatment will continue to receive it indefinitely.
The study will be conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines and local regulatory requirements in both the USA and UK. The appropriate institutional review boards will approve all trial documentation and any protocol changes made after study commencement will be recorded. All patients will be provided with written informed consent documentation.
Treatment Duration and End of Study
A complete treatment cycle will consist of 6 days of ATL-104 mouthwash (15ml at 50mg/ml, twice daily) or saline mouthwash (15ml, twice daily) administration and will commence following block randomisation at the start of chemo-/radio- therapy cycle. As a complete programme of therapy is expected to be for at least 6 months (and consist of ~8 therapy cycles), the study should be tracking these patients over the entire course of their treatment(s).
Patients will be recruited on a rolling basis and will commence their study treatment as and when they are due start a chemo- or radio- therapy cycle. This will reduce the chance of drop-outs as patients might otherwise be waiting for recruitment to complete before being allocated their study treatment. This means the whole trial will run for a considerable length of time but, this should ensure maximal recruitment and relevant data collection. Patients must be followed until evidence of WHO defined OM severity score change.
Patients will continue to receive ATL-104 mouthwash provided they derive clinical benefit from it.
Estimated Study period: Q1 2020 – Q1 2022
Estimated date of first patient enrolled: 10th January 2020 Estimated date of last patient completed: 30th January 2022
Collection of data will finish at the point the database is locked for statistical analysis by the data manager.
8 sites in the UK (An EU state at the time of writing) and 16 sites in USA will participate in this trial. This should provide significant recruitment opportunities and should ensure that patients are able to reach centre that is somewhat convenient for them, widening the potential recruitment pool.
The original UK-based Alizyme study (Clinicaltrials.gov, 2008) identified 8 specific sites across the UK. This has been the basis of this determination of UK centres.
A USA-based clinical trial into an oral rinse product of treatment of OM in HNC patients (Clinicaltrials.gov, 2019) identified 16 specific sites across the USA. This has been the basis of the determination of US centres.
All protocols and systems will be designed with MedDRA common language. Electronic Common Technical Documents (eCTD), electronic data capture and electronic Case Report Files (eCRF) will be used in order to facilitate good sharing of data across centres in line with ICH E6(R2).
Incidence of maximum severity OM on WHO and WCCNR scales. Duration of OM on WHO and WCCNR scales.
Area under the curve (AUC) of the mucositis score (Hunter et al., 2009).
Recording of additionally required hospitalisations related to OM.
Assessment of efficacy in other sub-populations of HNC patients as per EMA guidelines (EMA.europa.eu, 2019).
The primary end-point is the established standard for measuring OM severity (Hunter et al., 2009). A reduction in score from >=3 will result in clinically significant improvement in patients. A demonstration of this will provide the evidence to both regulators and commercial markets of efficacy.
The secondary end-points support the conclusions drawn from the primary end-point. AUC of mucositis score provides further context to the reduction in the OM severity scale.
The number of subsequent hospitalisations these patients require as a result of OM will be of particular interest to the market as this is where a considerable proportion of additional costs are deployed in the management of OM. Evidence that these have been reduced will further encourage the adoption of ATL-104 and its reimbursement.
The exploratory end-point aims to provide evidence of efficacy in other sub-populations of HNC patients. If efficacy can be demonstrated for other rare disease areas, this study can support further marketing indications in these orphan areas, increasing the success of ATL-104 as a marketable drug in a role as gold-standard for OM treatment and prevention.
Study drug: ATL-104 (+ current standard of care)
Dosage: 15ml at 50mg/ml concentration
Frequency: Twice daily
Control drug: Saline mouthwash (+ current standard of care) Dosage: 15ml Frequency: Twice daily One treatment cycle is equal to 6 consecutive days of dosing
Participants may continue treatment on an ongoing basis, provided they continue to derive clinical benefit.
· At least 18 years old on day of consent.
· All patients must demonstrate understanding of, and voluntarily sign the written informed consent before any study procedures commence. A copy of which will be retained by the treatment centre.
· All patients must be available for administration of treatment and any required follow-up.
· Negative pregnancy test (if female of childbearing potential).
· If female patient is of childbearing potential (or, in the case of a male participant, has a partner of child bearing potential), agree to the use of appropriate birth-control throughout their involvement in the study and for 3 months after their final treatment administration.
· Each patient must have received >=1 chemotherapy or radiation treatment before enrolment.
· Physical exam demonstrating evidence of oral mucositis severity equal or greater than 3 using the World Health Organization (WHO) Oral Mucositis Scale.
· Have a plan to receive a treatment course of conventional chemo- or radio- therapy.
· Have appropriate organ system function e.g. renal, hepatic, cardiovascular.
· Serious diagnosed uncontrolled co-morbidities for example, heart disease or a history of serious neurological conditions or psychiatric disorders.
· Evidence of significant renal, hepatic, hematologic, or immunologic disease.
· Has an ECG that demonstrates significant abnormality/ies.
· Has active infectious disease undergoing systemic treatment.
· Suffers from any condition or disorder that affects immune system function.
· Receives chronic administration of steroids
· Has had a significant, non-HNC related surgical procedure or injury in the month leading up to study commencement.
· Had OM before start of cancer therapy.
· Is pregnant or breastfeeding
· Has a sensitivity or intolerance to plant lectins
Patient Recruitment Strategy
Patients will be recruited through a number of routes.
We will have direct self-referrals from interested parties through work with advocacy and patient support groups.
Patients will also be recruited through consultant and specialist clinician referrals and their associated networks.
We will also identify facilities that have previously conducted or been involved in clinical trials in this treatment area to assist with local patient recruitment.
In addition to these traditional recruitment methods, we will conduct social media campaigns to try to reach patients that are targeted for marketing by the inclusion/exclusion criteria, demographic and geographic data available to us as per NIH guidelines on the use of social media (National Institutes of Health (NIH), n.d.). This has demonstrated to be an effective recruitment tool, especially when trying to target patients in hard-to-reach populations (Topolovec-Vranic and Natarajan, 2016).
We will also register with the National Institute for Health Research’s BePartOfResearch initiative in order to widen the potential scope of patient recruitment.
The use of multiple centres in both the UK and USA should increase the potential size for the patient population and we will target clinical trial sites that are in geographic proximity to cancer treatment centres, ideally targeting those in proximity to HNC specialist treatment centres, where these are available.
Study Analysis and Decision Making:
Interim analyses will be conducted by an Independent Data
Monitoring committee (IDMC) at Q1 2012, representing the half way point for the predicted study time. Where 0.0144 of α is ‘spent’, leaving α=0.0452 for the final analysis set. This will inform whether the study is likely to need extending and will allow an estimation of efficacy in the patient populations already recruited. If required, analysis at this stage may lead to a decision by the IDMC to reduce the study power to 80%, if insufficient patients are likely to be recruited for 90% power to be maintained.
The IDMC will also be convened when 50 patients have been enrolled and followed up for 3 months in order to conduct safety data reviews. These will continue on an annual basis where recommendations to continue, amend or discontinue to study can be made, if appropriate.
Final analysis will be conducted at the end of the trial period. The primary end-point is the reduction in OM severity score as per the WHO and WCCNR scales under the Intention to Treat (ITT) principle and an appropriate multiplicity framework in place.
SAEs, AEs and SUSARs will be immediately reported to the IDMC who will evaluate them and make referrals to the appropriate bodies, if required.
Sample Size Analysis:
248 patients (186 in active group and 62 in the control group) will be randomized in a 3:1 ratio (ATL-104 (+standard of care): Placebo (+standard of care)) in this study.
The sample size is based on figured from previous studies (Henke et al., 2011) and 25% reduction in severity being considered clinically significant (Clinicaltrials.gov, 2016). And provides a 14% dropout rate, 90% power and α=0.05 and β=0.1.
The intention to treat (ITT) principle will guide all statistical analysis carried out on trial data.
Reduction on OM severity score will be analysed using a log-rank test stratified by: Current standard of care, severity of OM as per WHO scale, sex, age, number of cancer treatment cycles already received and if applicable, specific sub-group of HNC (i.e. HPV, pharynx, larynx, nasopharynx and hypopharynx).
Mean reduction scores and standard deviations for these means will be calculated. Median and interquartile ranges will also be calculated to provide further context to the results. These two calculations will provide the measure of efficacy as per the primary end-point.
AUC of the OM severity scores will be calculated following a log-scale plot of the change in severity data which represents one of the secondary end-point measures.
The same mean and median calculations (including standard deviations and interquartile ranges) will be carried out to determine the frequency of further hospitalisations required by these patients as a result of their OM, which is the other secondary end-point measure.
Significance and Confidence:
95% confidence intervals will be calculated for all end-point analyses to determine the precision of the results. P-values will be calculated for intrapatient and interpatient comparisons, to provide context to the effect size in determining whether the observed change is statistically significant.
A 2-tailed, paired, T-Test will be carried out to determine the statistical significance of the change in OM severity between the two treatment groups. In addition to this, Standardized Mean Difference (SDM) and Cohen’s d will also be calculated in order to determine the observed effect-size of the OM severity reduction. Relative risk and Odds ratios will be calculated in order to support this determination (Faraone, 2008).
If sufficient patients in the other orphan disease sub-groups have been recruited to provide analysis of the efficacy of ATL-104 these patients will be included in their own analyses in the same areas.
Schedule of Assessments (per patient)
4. Consideration of the regulatory strategy
Part of the regulatory strategy has been outlined in Assignment 1 and is reproduced below:
“We plan to apply for orphan drug designation approval with the EMA and FDA. We will also seek parallel shared advice (PSA) from both agencies as per the SOPP 8001.6 guidance (FDA.gov, 2019) in order to ensure that approval requirements will be met expeditiously.
Clinical development work will be conducted both within the UK (an EU state at the time of writing) and the USA to ease this process and ensure sufficient patient recruitment. This parallel application will accelerate the process of introducing the product into other markets should the company wish to in the future. Additional benefits of the FDA Orphan Drug programme include 50% tax credits for trials, improved approval times and patent exclusivity for up to seven years (Cheung et al., 2004).
[..]Once ATL-104 has been successfully commercialised for its use in the HPV sub-group of HNC patients, the product could be further developed for other orphan cancer patient indications that suffer from OM for example pharynx, larynx, nasopharynx and hypopharynx HNCs which would all qualify for orphan designation from both the EMA and FDA as they affect less than 1 in 50,000 patients and affect less than 2000,000 patients in the US (ASHA.org, n.d.).
[..]The drug will be further developed for commercialisation and launched onto the American and European markets. Following the products’ establishment in these markets, marketing authorisation will be sought from the PMDA” (Wogman, D., 2019).
It may be the case that a bridging study is required for Japanese approval although, with a successful orphan drug designation, this should not be required. Although other drugs are available on the Japanese market for OM, ATL-104 should demonstrate greater efficacy is will be indicated for a narrow population of patients with HPV-related HNC and there should be primed for regulatory approval without the need for additional, local data to be generated (Sharma et al., 2010). The EU marketing strategy involves application with the UK as rapporteur. The MHRA standard should ensure that clinical trial data is accepted by other regulatory agencies (Kramer, Smith and Califf, 2012).
Following successful marketing authorisation, reimbursement will be sought from the relevant bodies for example, NICE in the UK. We will also seek approval from Medicare and Medicaid decision bodies in the US as well as, applying to major American insurance providers such as, the WellPoint Health Network. We anticipate good uptake of ATL-104 in both markets due to its demonstrated efficacy in treating OM and the secondary cost-savings anticipated by the treatment of this condition. The pricing strategy for ATL-104 also has this primed for reimbursement with relation to QALY based pricing measures outlined by NICE (NICE., 2017).
Bogaerts, J., Sydes, M., Keat, N., McConnell, A., Benson, A., Ho, A., Roth, A., Fortpied, C., Eng, C., Peckitt, C., Coens, C., Pettaway, C., Arnold, D., Hall, E., Marshall, E., Sclafani, F., Hatcher, H., Earl, H., Ray-Coquard, I., Paul, J., Blay, J., Whelan, J., Panageas, K., Wheatley, K., Harrington, K., Licitra, L., Billingham, L., Hensley, M., McCabe, M., Patel, P., Carvajal, R., Wilson, R., Glynne-Jones, R., McWilliams, R., Leyvraz, S., Rao, S., Nicholson, S., Filiaci, V., Negrouk, A., Lacombe, D., Dupont, E., Pauporté, I., Welch, J., Law, K., Trimble, T. and Seymour, M. (2015). Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative. European Journal of Cancer, 51(3), pp.271-281.
Clinicaltrials.gov. (2008). Safety, Tolerability and Efficacy of ATL-104 in Oral Mucositis - Full Text View - ClinicalTrials.gov. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT00163280 [Accessed 28 Nov. 2019].
Clinicaltrials.gov. (2016). Palifermin for the Reduction of Oral Mucositis in Patients With Locally Advanced Head and Neck Cancer - Study Results - ClinicalTrials.gov. [online] Available at: https://clinicaltrials.gov/ct2/show/results/NCT00101582 [Accessed 28 Nov. 2019].
Clinicaltrials.gov. (2019). Study of the Effects of Brilacidin Oral Rinse on Radiation-induced Oral Mucositis in Patients With Head and Neck Cancer - Full Text View - ClinicalTrials.gov. [online] Available at: https://clinicaltrials.gov/ct2/show/study/NCT02324335 [Accessed 28 Nov. 2019].
EMA.europa.eu. (2019). Guideline on the investigation of subgroups in confirmatory clinical trials. [online] Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-subgroups-confirmatory-clinical-trials_en.pdf [Accessed 29 Nov. 2019].
Faraone S. V. (2008). Interpreting estimates of treatment effects: implications for managed care. P & T : a peer-reviewed journal for formulary management, 33(12), 700–711.
Henke, M., Alfonsi, M., Foa, P., Giralt, J., Bardet, E., Cerezo, L., Salzwimmer, M., Lizambri, R., Emmerson, L., Chen, M. and Berger, D. (2011). Palifermin Decreases Severe Oral Mucositis of Patients Undergoing Postoperative Radiochemotherapy for Head and Neck Cancer: A Randomized, Placebo-Controlled Trial. Journal of Clinical Oncology, 29(20), pp.2815-2820.
Hunter, A., Mahendra, P., Wilson, K., Fields, P., Cook, G., Peniket, A., Crawley, C., Hickling, R. and Marcus, R. (2008). Treatment of oral mucositis after peripheral blood SCT with ATL-104 mouthwash: results from a randomized, double-blind, placebo-controlled trial. Bone Marrow Transplantation, 43(7), pp.563-569.
Kramer, J., Smith, P. and Califf, R. (2012). Impediments to Clinical Research in the United States. Clinical Pharmacology & Therapeutics, 91(3), pp.535-541.
National Institutes of Health (NIH). (n.d.). Guidance Regarding Social Media Tools. [online] Available at: https://www.nih.gov/health-information/nih-clinical-research-trials-you/guidance-regarding-social-media-tools [Accessed 29 Nov. 2019].
NICE. (2017). Changes to NICE drug appraisals: what you need to know. [online] Available at: https://www.nice.org.uk/news/feature/changes-to-nice-drug-appraisals-what-you-need-to-know [Accessed 25 Nov. 2019].
Röhrig, B., Prel, J., Wachtlin, D., Kwiecien, R. and Blettner, M. (2010). Sample Size Calculation in Clinical Trials. Deutsches Aerzteblatt Online.
Sharma, A., Jacob, A., Tandon, M. and Kumar, D. (2010). Orphan drug: Development trends and strategies. Journal of Pharmacy and Bioallied Sciences, 2(4), p.290.
Wogman, D. (2019). CLD – Assignment 1. Drug Development Science MSc.
Topolovec-Vranic, J. and Natarajan, K. (2016). The Use of Social Media in Recruitment for Medical Research Studies: A Scoping Review. Journal of Medical Internet Research, 18(11), p.e286.
An assignment by: Darren Wogman MSc. Completed as part of Pharmaceutical Medicine MSc at King's College London