Oral chemotherapy is a convenient and flexible option for cancer treatment that can improve patients quality of life and increase adherence to treatment compared to traditional intravenous chemotherapy. However, since patients are responsible for taking the medication, there can be issues with continuity and adherence. Like other medications, generics of existing oral chemotherapy have emerged, which help reduce costs and improve access to this therapy. These generics contribute to a more sustainable healthcare system, so it is necessary to implement effective strategies for their adoption.

Although generic treatments have been shown to be just as effective as the original drug, there is no regulation requiring the pill to have the same shape and color as the original (what we refer to as appearance). Additionally, the packaging of the treatment is different as it is specific to each brand. Therefore, a patient on a specific treatment may switch from the original medication to a generic or from one generic to another, which may have a different appearance in both the pill and the packaging.

It has been observed that these changes can lead to medication errors or a loss of patient confidence, resulting in decreased continuity and adherence to treatment. These issues have been seen with other medications for chronic diseases but have not been studied in cancer patients to date. In these patients, despite the nature of the disease suggesting they would be adherent to treatment, previous studies have shown that this is not the case, with only about 70% of patients being adherent. This lack of adherence affects treatment efficacy, increases the risk of disease relapse, and therefore negatively impacts patient s quality of life and survival while also increasing costs.

Therefore, this study focuses on evaluating whether these changes in pill appearance and/or packaging impact treatment continuity and adherence, as well as other relevant patient outcomes and their experience with the healthcare received. Additionally, we want to analyze whether there are patient variables (such as health literacy, age, or clinical variables) that influence the impact of these changes. Given the differences in adherence between men and women, it is essential to conduct these analyses separately for both genders.

The results obtained from this study will contribute to the development of educational strategies for managing oral chemotherapy by patients and healthcare professionals. Additionally, new evidence will be generated to allow decision-makers to establish policies, either by choosing treatments with the least change in appearance or by regulating the appearance of treatments. All of this will contribute to greater treatment effectiveness, improved patient quality of life, and a lower rate of disease recurrence.

The project "APAR-AdhNEO" aims to evaluate the impact of a change in appearance (changes in shape and/or color of the tablet and/or packaging) of the prescribed oral antineoplastic (ANEO) (whether switching from brand-name to generic or between generics) on the patient's healthcare experience, treatment continuity and adherence, as well as patient-reported outcomes, and whether this differs between men and women.

Study Design Specifications The study follows a mixed-methods design. For secondary outcome 1 (secondary outcomes described in outcomes measure section), a prospective study will be designed to evaluate the frequency of changes in ANEO prescriptions. For secondary outcomes 2-5, a before-and-after study will be conducted to assess the impact of medication changes on various variables.

As part of the study evaluating the patient s experience with healthcare (secondary outcome 2), in addition to quantitatively assessing this experience before and after the change, a qualitative study will be conducted using focus groups with patients.

Sample Size Estimation According to a systematic review conducted by the research team, the frequency of non-adherence and/or treatment discontinuation after a change in appearance and/or packaging varies across studies. For example, a change in appearance was associated with a reduction in adherence to antihypertensive treatment (from 69% to 50%), preventive treatment for heart attacks (from 97% to 87%), and olanzapine treatment (from 28% to 16.7%), Another study on antidiabetics showed that the number of patients who discontinued their treatment after a medication change increased from 62% to 72%.

Moreover, a previous study conducted by the research team showed that adherence to ANEO treatment, evaluated using the EXPAD-ANEO scale and pill counting, was 69.3%.

Therefore, considering the ANEO treatment adherence of our patient population (69.3%) and to detect a change in adherence similar to that analyzed in previous studies (at least 10%) when a medication appearance change occurs, with a statistical power of 80% and a 95% confidence level, we would need to include 284 patients. Considering a potential 15% loss of patients during follow-up, we will increase the sample size to 334 patients.

Study Procedure

• To reach secondary outcome 1 Procedure: Through the records of the Hospital Pharmacy Service.

• To reach secondary outcomes 2-5 Procedure: When a change in any of the included ANEOs (from brand to generic or between generics) is about to occur, patients who meet the selection criteria and are scheduled to receive the new medication at their next dispensing will be contacted. The study will be explained to them, and their oral informed consent will be requested. They will be asked to bring their last dispensed medication to the Pharmacy Service for a pill count (this is a routine practice in the service, but they will be reminded to bring it).

  • During the baseline visit (in the pharmacy service), the patient will receive written informed consent and detailed information about the study. Data will be collected on: a) Continuity of treatment over the previous six months and details of the change (pharmacy records); b) Disease and treatment characteristics (patient history); c) Sociodemographic data; d) Health literacy; e) Adherence assessment; f) PROMs and PREMs values (patient interview).
  • Follow-up assessments will be conducted at three and six months to evaluate changes in adherence, continuity, PREMs, and PROMs.

• To reach secondary qualitative outcome 2 Procedure: Through the FORO patient group. Data Analysis

• Quantitative Analysis

  • Secondary outcome 1 The total frequency of changes during the study period will be evaluated by type of medication, change, and cause.
  • Secondary outcome 2-5 The change in treatment continuity, adherence, and PREMs and PROMs assessments will be evaluated based on the characteristics of the medication change and patient characteristics for both men and women.

The association between each independent variable and the dependent variables (treatment continuity change, adherence, and PREMs and PROMs assessments for each patient) will be studied using Pearson's Chi-squared test or Fisher's exact test, and the Student's T-test or the non-parametric Mann-Whitney U-test to compare means. The impact of medication change on treatment continuity, adherence, and PROMs and PREMs assessments will be analyzed through multivariate analysis using a Cox proportional hazards model. Covariates considered in the models will include those sociodemographic and clinical patient variables that modify the risk by more than 10% and have been associated with previous bivariate analysis. P-values <0.05 will be considered statistically significant. These analyses will be conducted separately for men and women.

• Qualitative Analysis

o Secondary outcome 2 Two researchers will triangulate the information obtained from the different groups. First, a careful reading of the transcription will be performed, and the text will be divided into meaningful information units. These units will be coded following a mixed strategy (emerging codes and predefined codes according to the study objectives), and categories will be developed based on the grouping of codes with the same theme. Finally, points of agreement and disagreement will be analyzed.

Data Management

A data management plan will be developed at the beginning of the project to establish how the data will be processed and managed throughout the project and how they will be stored after the project is completed. A brief description is provided below:

Regarding the type and format of data, various data will be generated using qualitative and quantitative methodology.

For secondary outcome 2, data on the sociodemographic and professional characteristics of the participants in the discussion groups and transcripts of their discussions will be collected.

For secondary outcomes 2-5, sociodemographic data of the patients included in the study will be collected. A database with individualized information on the 334 oncology patients undergoing treatment with the indicated ANEOs will be created.

All data collected during the project, as well as those generated from the project, will be pseudo-anonymized. No record will lead to the individual identification of participants. If any personal data are shared by participants in the discussion groups, they will not be transcribed. All participants will have previously signed informed consent, and if a person decides to revoke their consent later, all data related to that person will be deleted.

During the study, the data generated will be the property of UMH and will be stored in the university's information systems. Access will be granted through username/password. After the study concludes and the research is published, raw data and transcripts will be stored in an open repository such as Zenodo, complying with FAIR principles to ensure that they are accessible, reusable, and interoperable. This step will facilitate data sharing and reuse, which may accelerate research and promote innovation.

Objective 1:

Inclusion criteria:

ANEOs included in the pharmacotherapeutic guide of the three hospitals for two years of follow-up (June 2025-2027) will be included.

Objectives 2-5:

Inclusion criteria:

• Patients on treatment for at least 6 months with one of the following ANEOs will be included: capecitabine (L01BC06) (not used as adjuvant in short cycles), imatinib (L01EA01), everolimus (L04AA18), abiraterone (L02BX03) and lenalidomide (L04AX04), at the time of a change in their usual treatment (from brand to generic or between two generics).
• Patients on treatment with ANEOs who meet the established criteria and who change their treatment from brand to generic or from one generic to another generic during the study period may also be included.

Exclusion criteria:

• Individuals who collect medication for others and those who are institutionalised will be excluded.
• Patients who have been admitted to hospital in the last 4 weeks are also excluded, due to the increased control of their medication.

Objective 2( Qualitative analysis)

- Spanish Patient Forum

The 2023 data from the hospitals where the study will be carried out shows that 517 patients were treated with one of the ANEOs included in the study. Given the required sample size of 334 patients, 112 patients will be consecutively admitted to each hospital, including those who meet the eligibility criteria, and will be followed for six months. For the qualitative investigation of objective 2 and participation in the focus groups, cancer patients treated with ANEOs will be contacted via the Spanish Patient Forum (3 gruops, 8-12 participants each)