RESUMEN

A fin de identificar las características de los ensayos clínicos oncológicos presentados ante el Instituto Nacional de Salud del Perú en el periodo 1995-2019, se realizó un estudio observacional descriptivo, evaluando la información contenida en el Registro Peruano de Ensayos Clínicos. Se identificaron 1996 ensayos clínicos de los cuales 470 eran oncológicos (23,5%); el 74,9% de los ensayos clínicos oncológicos fue patrocinado principalmente por la industria farmacéutica, el 61,9% fue de fase III, siendo autorizados el 86,2%. Entre los autorizados, el 55,6% eran productos de investigación de tipo químico, el 35,9% correspondieron a indicación terapéutica para cáncer de mama; el principal diseño fue de grupos paralelos (84,7%), aleatorizados (85,2%), cegados (51,0%), el criterio de valoración principal más empleado fue la tasa de respuesta objetiva (46,7%). Se concluye que los ensayos clínicos oncológicos se han ido incrementando con los años, con frecuencia diversa entre sus características.

Palabras clave:
Características del Estudio; Cáncer; Ensayo Clínico

ABSTRACT

A descriptive observational study was carried out to identify the characteristics of the oncological clinical trials submitted to the Instituto Nacional de Salud del Perú during the period from 1995 to 2019. The information was obtained from the Peruvian Registry of Clinical Trials. We identified 1,996 clinical trials during the studied period, from which 470 were oncological (23.5%); 74.9% of the oncological clinical trials were mainly sponsored by the pharmaceutical industry, 61.9% were phase III and 86.2% were authorized. Regarding those authorized clinical trials, 55.6% were on chemical research products and 35.9% were on therapeutic indication for breast cancer. The most frequent study designs found were: parallel arm (84.7%), randomized (85.2%) and blinded (51.0%); the most frequently used main endpoint was the objective response rate (46.7%). We conclude that the number of oncological clinical trials has been increasing over the years, often with different characteristics.

Keywords:
Study Characteristics; Neoplasms; Clinical Trial

INTRODUCTION

Clinical trials (CT) that address oncological issues have found a favorable scenario to evaluate effective therapeutic and/or palliative treatment alternatives, taking into account the different stages of the disease ¹1. Sotelo-Rodríguez DC, Ruíz-Patiño A, Ricaurte L, Arrieta O, Zatarain-Barrón ZL, Cardona AF. Challenges and shifting paradigms in clinical trials in oncology: the case for immunological and targeted therapies. Ecancer. 2019;13:936. doi: 10.3332/ecancer.2019.936.
https://doi.org/10.3332/ecancer.2019.936... . This is because, cancer is currently considered a global public health problem ²2. Unger JM, Cook E, Tai E, Bleyer A. The Role of Clinical Trial Participation in Cancer Research: Barriers, Evidence, and Strategies. Am Soc Clin Oncol Educ Book. 2016;36:185-98. doi: 10.1200/EDBK_156686.
https://doi.org/10.1200/EDBK_156686... .

Some CT regulatory agencies, beyond their well-known functions of providing the legal framework and safeguarding the integrity of research subjects, have implemented open databases with information on all the CTs they register and authorize. In this regard, the World Health Organization (WHO) manages the International Clinical Trials Registry Platform (ICTRP) https://apps.who.int/trialsearch/Default.aspx), in order to ensure free access to information³3. Ogino D, Takahashi K, Sato H. Characteristics of clinical trial websites: information distribution between ClinicalTrials.gov and 13 primary registries in the WHO registry network. Trials. 2014;15(1):428. doi: 10.1186/1745-6215-15-428.
https://doi.org/10.1186/1745-6215-15-428... .

This and other databases that consolidate information on CTs around the world have been the subject of research that seeks to identify how the frequency of CTs around the world has varied. Viergever et al. identified a steady increase in the number of reported CTs, from 3,294 in 2004 to 23,384 in 2013, although these figures include all types of CTs (oncological and non-oncological) ⁽⁴4. Viergever RF, Li K. Trends in global clinical trial registration: an analysis of numbers of registered clinical trials in different parts of the world from 2004 to 2013. BMJ Open. 2015;5(9):e008932. doi: 10.1136/bmjopen-2015-008932.
https://doi.org/10.1136/bmjopen-2015-008... .

In Peru, the Instituto Nacional de Salud (INS), as the regulatory authority for clinical trials in the country, has been operating the Peruvian Registry of Clinical Trials (REPEC) since 2007. This database has been used by previous studies to characterize CTs. According to the general report by Minaya et al. for the period 1995-2012 ⁵5. Minaya G, Fuentes D, Obregón C, Ayala-Quintanilla B, Yagui M. Características de los ensayos clínicos autorizados en el Perú, 1995-2012. Rev Peru Med Exp Salud Publica. 2012;29(4):431-36. doi: 10.1590/s1726-46342012000400003.
https://doi.org/10.1590/s1726-4634201200... and by Alarcón Ruiz et al. for 1995-2017 ⁶6. Alarcon-Ruiz CA, Roque-Roque JS, Heredia P, Góme-Briceño AR, Quispe AM. Twenty-two years' experience registering trials in a low-middle income country: The Peruvian Clinical Trial Registry. J Evid Based Med. 2019;12(3):187-93. doi: 10.1111/jebm.12354.
https://doi.org/10.1111/jebm.12354... , it is known that cancer-related CTs are the most frequent in the country.

Although these are public databases and are available for all researchers, it was not possible to identify published studies on relevant aspects of the CTs that are oriented to oncological pathologies in Peru. Therefore, the aim of this research was to identify the characteristics of oncological clinical trials (OCT) reported in a 25-year period (1995 to 2019).

THE STUDY

We carried out an observational and descriptive study to evaluate the characteristics of oncology-related clinical trials that were submitted to the General Office of Research and Technology Transfer (OGITT) of the INS for evaluation and authorization between 1995 and December 31, 2019. The public information found in the REPEC was reviewed and freely accessed through the portal https://ensayosclinicos-repec.ins.gob.pe; the last review was carried out on January 3, 2020. The records found were collected in a database for analysis.

The variables evaluated in the OCTs were grouped into general, design, and studied product characteristics. The general characteristics included type of sponsor, trial status, number of Research Ethics Committees (RECs) that approved the OCT, and number of research centers where the study was conducted.

Sponsors were grouped into five categories: cooperative groups (research networks, scientific societies, civil associations, foundations and research organizations), pharmaceutical industry (industries, laboratories and companies), national health institutes (both in Peru and abroad) and universities (public and private, national and foreign). The status of the trials were grouped into three categories: authorized (active, partial suspension, early termination, finished, suspended after authorization, canceled), unauthorized and others (process without effect, suspended before obtaining authorization, declared in abandonment, declared as withdrawal, declared unsuitable, under evaluation).

Regarding design characteristics of the OCTs, we considered phase of the trial, the specific design, type of blinding, type of randomization and the main endpoint. Regarding the studied product’s characteristics, we considered the type of product and the medical indication.

Design and studied product’s characteristics were analyzed in all OCTs submitted and in those authorized. Data not found were considered as “not registered” (NR).

Data collected was evaluated with the statistical program Stata V16.1 (Stata Corporation, College Station, Texas, USA) and qualitative variables were described with descriptive summary measures of proportions (%). No statistical imputation processes or inferential tests were carried out.

This study did not require the approval of an ethics committee, since it was a secondary analysis of a free access-database, and because it did not contain data that could identify the subjects.

FINDINGS

We identified 1,996 CTs from the period 1995-2019, of which 470 were oncological (23.5%); the first records were submitted in 1999 (n = 8; 1.7%). The number of CTs varies per year; it was evident that between 1999 and 2002 there were less than 20 per year. Then we observed a constant increase until 2008, when the maximum peak occurred (n = 50; 10.6%) and after this year the number of CTs progressively decreased in the following years. In spite of this, the proportion of OCTs submitted, with respect to the total number of CTs, has increased during the evaluated period (Figure 1).

Regarding the general characteristics of the OCTs, we found that the most frequent type of sponsor was the pharmaceutical industry (74.9%). Most OCTs were authorized (n = 405; 86.2%), of which 61.2% were finished (n = 248). Nearly half (49.6%) of the OCTs were approved by only one REC and the most frequent (n = 249; 26.7%) was the one from the Instituto Nacional de Enfermedades Neoplásicas (INEN). Most of the OCTs (38.1%) were conducted in only one research center. The highest number of research locations for a single study was 14 (Table 1). The proportion of authorized OCTs varied over the years, with a tendency towards an irregular decrease (Supplementary material).

Regarding the design characteristics, most of the OCTs were in phase III, followed by phase II; the most used specific design was parallel groups (84.5%), adaptive CTs were the least frequent ones (basket = 0.4%, umbrella = 0.2). Among the authorized OCTs, open-label and double-blind CTs were found in similar frequency (47.9 and 46.4%, respectively); 85.2% were randomized (Table 2).

During the analysis of the studied product’s characteristics, we found that chemical products were the most frequent among the authorized OCTs (55.6%). Regarding the indication of the product, we found that most were therapeutic (91.4%) and those aimed at breast cancer (35.9%) stand out. Among those with palliative indications, products for emesis (45.7%) and pain (34.3%) were the most frequent. The most used main endpoint was the objective response rate, which was used in 47.0% of all the trials and 46.7% among those authorized (Table 3).

DISCUSSION

We identified that the number of OCTs submitted has varied annually. However, considering the proportion of OCTs with respect to the total number of registered CTs, an upward trend was evident, by 2019 these represented almost 50%. This behavior is not specific to Peru, according to the data registered in ClinicalTrials.gov and EudraCT, we found similar distributions in other countries ⁷7. The Lancet Oncology. Clinical trial registry reporting: a transparent solution needed. The Lancet Oncology. 2019;20(6):741. doi: 10.1016/S1470-2045(19)30350-X.
https://doi.org/10.1016/S1470-2045(19)30... .

In the 25-year period that was analyzed, we found that 23.5% of the CTs were oncological; this figure is similar to the 22.4% reported by Minaya et al. ⁵5. Minaya G, Fuentes D, Obregón C, Ayala-Quintanilla B, Yagui M. Características de los ensayos clínicos autorizados en el Perú, 1995-2012. Rev Peru Med Exp Salud Publica. 2012;29(4):431-36. doi: 10.1590/s1726-46342012000400003.
https://doi.org/10.1590/s1726-4634201200... for the period 1995-2012. These results show the significant presence of this type of research in our country over time, slightly higher than the 21.8% found in ClinicalTrials.gov for the period 2007-2010 ⁸8. Hirsch BR, Califf RM, Cheng SK, Tasneem A, Horton J, Chiswell K, et al. Characteristics of Oncology Clinical Trials: Insights From a Systematic Analysis of ClinicalTrials.gov. JAMA Intern Med. 2013;173(11):972. doi: 10.1001/jamainternmed.2013.627.
https://doi.org/10.1001/jamainternmed.20... .

On the other hand, the studied products were mostly for therapeutic use (91.9%), aimed at the treatment of breast and lung cancer. These findings are consistent with the analysis of Minaya et al. ⁵5. Minaya G, Fuentes D, Obregón C, Ayala-Quintanilla B, Yagui M. Características de los ensayos clínicos autorizados en el Perú, 1995-2012. Rev Peru Med Exp Salud Publica. 2012;29(4):431-36. doi: 10.1590/s1726-46342012000400003.
https://doi.org/10.1590/s1726-4634201200... ^), and reflect the high incidence of these types of cancer in the world⁹9. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. doi: 10.3322/caac.21492.
https://doi.org/10.3322/caac.21492... . The high morbimortality of cancer has encouraged the production of OCTs on diagnostic methods, like for example the study of the efficacy of the folate receptor-mediated staining solution as a tool for early detection of cervical cancer ¹⁰10. Zhao Y, Li M, Li Y, Lv Q, Chen F, Li B, et al. Evaluation of Folate Receptor-Mediated Cervical Dyeing as a Method for Detection of Cervical Lesions: Journal of Lower Genital Tract Disease. 2019;23(2):133-7. doi: 10.1097/LGT.0000000000000411.
https://doi.org/10.1097/LGT.000000000000... , or the use of new “digital tomosynthesis” equipment for the systematic identification of breast cancer ¹¹11. SOS Study team, Chauvie S, De Maggi A, Baralis I, Dalmasso F, Berchialla P, et al. Artificial intelligence and radiomics enhance the positive predictive value of digital chest tomosynthesis for lung cancer detection within SOS clinical trial. Eur Radiol. 2020;30(7):4134-40. doi: 10.1007/s00330-020-06783-z.
https://doi.org/10.1007/s00330-020-06783... .

Most Peruvian CTs were sponsored by the pharmaceutical industry. A similar pattern is evident in Western European countries, where for the period 2007-2015; 74% of the CTs had commercial sponsorship ¹²12. Dombernowsky T, Hædersdal M, Lassen U, Thomsen SF. Development in the number of clinical trial applications in Western Europe from 2007 to 2015: retrospective study of data from national competent authorities. BMJ Open. 2017;7(7):e015579. doi: 10.1136/bmjopen-2016-015579.
https://doi.org/10.1136/bmjopen-2016-015... . Participation of the pharmaceutical industry in the research of new cancer drugs is not something new; this type of financing has already been identified and has shown favorable results in these studies ¹³13. Al-Badriyeh D, Alameri M, Al-Okka R. Cost-effectiveness research in cancer therapy: a systematic review of literature trends, methods and the influence of funding. BMJ Open. 2017;7(1):e012648. doi: 10.1136/bmjopen-2016-012648.
https://doi.org/10.1136/bmjopen-2016-012... .

During the last two years, two new OCTs designs have been registered; these adaptive designs or so-called “Master Protocols”, are classified as Basket (defined by cohorts with different types of tumors assigned to the same treatment), and Umbrella (defined by cohorts with the presence of the same type of tumor with or without associated biomarkers that receive different treatments) ¹⁴14. Goldberg RM, Wei L, Fernandez S. The Evolution of Clinical Trials in Oncology: Defining Who Benefits from New Drugs Using Innovative Study Designs. The Oncol. 2017;22(9):1015-9. doi: 10.1634/theoncologist.2017-0153.
https://doi.org/10.1634/theoncologist.20... ^,1515. Sudhop T, Brun NC, Riedel C, Rosso A, Broich K, Senderovitz T. Master protocols in clinical trials: a universal Swiss Army knife? The Lancet Oncology. 2019;20(6):e336-42. doi: 10.1016/S1470-2045(19)30271-2.
https://doi.org/10.1016/S1470-2045(19)30... . These adaptive designs, together with the Platform type (not yet registered in our country), have been increasingly adopted worldwide since 2001 as an alternative for OCTs; and are more frequent in the United States ¹⁶16. Park JJH, Siden E, Zoratti MJ, Dron L, Harari O, Singer J, et al. Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols. Trials. 2019;20(1):572. doi: 10.1186/s13063-019-3664-1.
https://doi.org/10.1186/s13063-019-3664-... .

Traditionally, the main endpoints used in the OCTs were clinical improvement measures, such as the improvement of signs and/or symptoms, and the patient’s quality of life ¹⁷17. Kilickap S, Demirci U, Karadurmus N, Dogan M, Akinci B, Sendur MAN. Endpoints in oncology clinical trials. JBUON. 2018; 23(s1):1-6.. However, during the last decade, sponsors have used other criteria to achieve the accelerated approval of anti-cancer drugs, among these we have the tumor shrinkage evaluation and tumor growth retardation ¹⁸18. Wilson MK, Karakasis K, Oza AM. Outcomes and endpoints in trials of cancer treatment: the past, present, and future. The Lancet Oncology. 2015;16(1):e32-42. doi: 10.1016/S1470-2045(14)70375-4.
https://doi.org/10.1016/S1470-2045(14)70... . Given this scenario, regulatory agencies have been in charge of evaluating the relevance, case by case, of the use of substitute endpoints and of providing guidelines for reasonable use ¹⁹19. Food and Drug Administration. Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics [Internet]. Maryland: Estados Unidos. Departamento de Salud y Servicios Sociales; 2018. Disponible en: https://www.fda.gov/media/71195/download.
https://www.fda.gov/media/71195/download... . All of this has meant that currently the main endpoints used for these studies are the objective response rate, or progression-free survival, considering that the need for their use will always depend on the context of the disease and the magnitude of the effect, among other factors ²⁰20. Kamat AM, Sylvester RJ, Böhle A, Palou J, Lamm DL, Brausi M, et al. Definitions, End Points, and Clinical Trial Designs for Non-Muscle-Invasive Bladder Cancer: Recommendations From the International Bladder Cancer Group. JCO. 2016;34(16):1935-44. doi: 10.1200/JCO.2015.64.4070.
https://doi.org/10.1200/JCO.2015.64.4070... .

A limitation of this study was that the information comes from what was registered in the REPEC, a platform created in 2007, which has been collecting data retrospectively on CTs that had previously been evaluated and authorized by the Ministerio de Salud. This leads to a possible information bias for data from the period 1995-2006. Despite this limitation, this study characterizes the most frequent group of CTs presented in our country in the last 25 years.

In conclusion, the frequency of the OCTs in Peru shows variations during the evaluated period, although proportionally an ascending behavior has been evidenced over the years. It was also possible to identify that phase II and III OCTs are the most frequent in our country. We evidenced that most studied products were for therapeutic use and were aimed at breast cancer.

The identification of OCTs with adaptive designs represents a challenge for ethics committees, patients, researchers and regulatory authorities alike. For this reason, in compliance with its role as the governing body in the area of CTs, the INS is called upon to establish training activities that guarantee an adequate implementation in our country.

References

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