Our proposed implementation focuses on the rural area application and coverage. We have integrated expert advice and our own considerations in our process. Here are the results of our discussions:

1. Proposed Product Mechanism

People could buy our product in pharmacies or it could be distributed by the government in an early screening program with a form of single capsule in blister packaging. The first step is to consume the capsule by drinking it with water. The enteric coating of the capsule will make sure the modified EcN inside the capsule will be safe until it reaches the intestine. In the intestine, the capsule will break down and the modified EcN will colonize the surrounding tissue, preferably the CRC tissue if present [1]. While colonizing, the modified EcN will also express the LIRA biodevice system into its secondary RNA structure. If there’s miR-21 or miR-92a present in the surrounding tissue, the LIRA will be able to bind with it, exposing the Ribosome Binding Site (RBS) and expressing the aeBlue chromoprotein gene. This chromoprotein will accumulate inside the modified EcN and since E. coli is observed to be increasing in the CRC patient feces, the modified EcN will also be accumulated and the blue color in from the aeBlue will be observed in the feces of the person. The whole process might need at least 12 hours to be able to be seen in the feces, depending on the diet of the person. Then the person will need to check the color by using the strip from the back of the packaging that serves as the positive control. If it has a matching color then the test result is positive. Since this product is only for an early screening, the person with a positive result will still need to be clarified by using a more accurate diagnosis method.

2. Proposed End-Users

Data from Global Cancer Statistics 2020 shows that the combination of colon and rectum cancer holds for approximately 10% (1,880,725) and 9% (915,880) of all cancer incidence and death in the world respectively [1].
In Indonesia, colorectal cancer stands at rank 4th and 5th of the most incidence and deaths respectively in Indonesia. It holds approximately 8.4% (33,427) and 7.6% (17,786) of all cancer incidence and death in Indonesia respectively [2].
Whereas, data from the Jogja Cancer Registry indicate that CRC ranks as the second among the most frequently encountered cancer cases in Yogyakarta [3].
The presented number of cases might be under-reported since people from rural areas need to go to the city to receive proper diagnosis. Not to mention other challenges such as the socioeconomic status and the awareness of the rural population to cancer screening. Although some primary healthcare providers from the government have been conducting a CRC screening program, the attendance is low because of how the product needs the company of healthcare professionals but since most of the rural population work in the morning to evening in the field, they can’t attend the screening program. This is why our product could help better by providing an easy procedure for the elderly to test themselves without the need of healthcare professionals. The Ministry of Health also recommends the elderly from the age of 50 to conduct a routine screening program for CRC [5].
Thus, our proposed end-users are the elderly from the age of 50 in rural areas that are still working.

3. Product Registration

In order to obtain the license, we need to register our product with the national authorization. We attempted to contact the Ministry of Health once again to inquire about the requirements for registration, but as of October 10th, we have not received a response from them. This has impeded our progress in planning for the registration of our product. Furthermore, it highlights the absence of concrete regulations for diagnostic products like ours.

4. Scale Up Manufacturing

Based on our discussion with Ms. Endang who has been developing her research team probiotics, we plan to use the similar approach as what she used. We plan to manufacture the modified EcN in conventional methods first to acquire the data needed for scale up to industrial scale (Figure 1) [6]. First and foremost, the modified EcN is inoculated into the mother flask for some time before inoculated again in the fermenter at the optimal condition. Since we plan to use the same method as Ms. Endang, we will use a fermenter with a working capacity of 168L with the media composed of meat and pineapple extract according to Ms. Endang. The fermentation will be left for a day and then the resulting fermentation will be centrifuged to acquire the cell biomass. The biomass will then be added with skim milk and sucrose as the cryoprotectant agent Ms. Endang advised us to use it. In addition, the concentration of the bacteria needs to be adjusted to contain 1x10^10 CFU/3 gram of mixture. The mixture was then put into the freeze drying chamber. The resulting powder will then be divided into the capsule and then packaged with the primary packaging which is blister. This method will also be used for the preclinical studies needed for the registration of our product.
Figure 1. Overview of manufacturing process of probiotic [6]

5. Cost-Effective Analysis

Since the end game of our project is to develop a partnership with the national screening program, we need to evaluate the proposed pharmacoeconomic model of our product. Cost-effectiveness analysis of a proposed CRC method is important to make a decision at the national level. A method is considered as “dominant” (cost-saving) when it gives a higher outcome with lower cost compared to the other method. While it is considered as “dominated” when it gives a lower outcome with higher cost [7]. When a method gives a higher outcome with higher cost, or vice versa, the cost-effectivity must be measured with incremental cost-effectiveness ratio (ICER). A method is considered as cost-effective if the ICER is below the threshold. According to WHO (2012) [8], for middle income countries, the recommended threshold is 1 to 3 times of gross domestic product (GDP) per capita. Indonesia GDP per capita is IDR 59.3 millions [9], it means that a screening method with ICER below 59.3 millions IDR will be considered as cost-effective.
To measure the outcome of colorectal cancer screening methods, Dr. apt. Dwi Endarti, M.Sc. suggested us to use sensitivity and specificity as the parameters of effectivity. Sensitivity and specificity of ColDBlu was estimated by averaging the sensitivity and the specificity from previous research [10,11,12]. Meanwhile, FOBT, FIT, sigmoidoscopy, and colonoscopy sensitivity and specificity were obtained from Knudsen et al. [13,14].
We also tried to estimate the cost of the ColDBlue test kit based on our discussion with Prof. Dr. Ir. Endang Sutriswati Rahayu, M.S., a probiotic expert with experience in developing probiotic products into industrial scale. She showed us the formula she used to calculate her probiotic product and since our product is manufactured the same way as probiotic, we used the same formula as her. However, since her product now has been adapted to the industry, we can’t publish the detailed formula we used. In summary, the cost of manufacturing a product can be divided into 4 different categories. Direct material cost represents all the material cost, Direct labor represents the labor price needed, manufacturing overheads represent all indirect cost needed for the manufacturing including the rent, taxes, and machinery, lastly is profit to make sure the project will be sustainable to the manufacturer. We propose a total of 1000 capsules per batch based on Ms. Endang’s experience (Table 1).
Direct material costRp2,000,000Rp2,000
Direct labourRp5,000,000Rp5,000
Manufacturing overheadsRp5,000,000Rp5,000
Total costRp14,500
Table 1. Estimated cost of ColDBlue test kit
Cost-effectiveness of ColDBlu was analyzed by comparing the cost and outcome (sensitivity or specificity) of ColDBlu with other screening methods that were currently used in Indonesia. Cost of the screening methods were calculated in patient perspective (IDR), considering direct medical costs (kit price and medical provider cost), direct non medical cost (transportation cost), and indirect cost (productivity loss). From the calculation, ColDBlu is considered as cost-saving compared to the other screening methods (FOBT, FIT, sigmoidoscopy, and colonoscopy) because it gives higher sensitivity with lower cost. However, the cost-effectiveness of ColDBlu to obtain additional specificity compared to other methods needs to be calculated by ICER because it costs lower but also gives lower specificity.
Table 2. Cost and outcome of ColDBlu and colorectal cancer screening methods in Indonesia
ICER was measured by dividing the incremental cost by incremental outcome (specificity) of ColDBlu and other methods separately. The measured ICER (cost per additional specificity gained) of ColDBlu compare to FOBT, FIT, sigmoidoscopy, and colonoscopy were IDR 364,424; 80,858; 3,558,361; and 5,623,464 respectively. Since the ICERs were below IDR 59.3 millions (GDP of Indonesia), ColDBlu is considered as cost-effective. Hence, ColDBlu can be implemented in the national setting as an affordable colorectal cancer screening method in Indonesia, especially the rural areas.
Table 3. ICER of ColDBlu to other applied colorectal cancer screening methods in Indonesia

6. Future Considerations

For the future of our project we need to develop a plan for these consideration:
  1. Kill switch
    To further ensure the safety of our product, we need to design a kill switch for the modified EcN. This will confirm that most of the modified EcN will be dead after the screening process.
[1] Chiang CJ, Huang PH. Metabolic engineering of probiotic Escherichia coli for cytolytic therapy of tumors. Scientific reports. 2021 Mar 12;11(1):5853.
[2] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians. 2021 May;71(3):209-49.
[3] Globocan 2020. Indonesia. World Health Organization; 2021 [cited 2023 September 27]. Available from:
[4] Jogja Cancer Registry. RKBR Maret 2022 – [Internet]. Jogja Cancer Registry. 2022 [cited 2023 May 5]. Available from:
[5] Indonesian Ministry of Health. [Internet]. KEPUTUSAN MENTERI KESEHATAN REPUBLIK INDONESIA NOMOR HK.01.07/MENKES/406/2018. 2018 [cited 2023 October 10]. Available from:
[6] Kumar V, Naik B, Kumar A, Khanduri N, Rustagi S, Kumar S. Probiotics media: Significance, challenges, and future perspective-a mini review. Food Production, Processing and Nutrition. 2022 Dec;4(1):1-3.
[7] Antonides CF, Cohen DJ, Osnabrugge RL. Statistical primer: a cost–effectiveness analysis. European Journal of Cardio-Thoracic Surgery. 2018 Aug 1;54(2):209-13.
[8] World Health Organization. World Health Organization, cost-effectiveness thresholds. 2012. [cited 2023 October 05]. Available from:
[9] Portal Informasi Indonesia. Indonesia Naik Kelas. Portal Informasi Indonesia. 2023 [cited 2023 October 05]. Available from:
[10] Moody L, He H, Pan YX, Chen H. Methods and novel technology for microRNA quantification in colorectal cancer screening. Clinical epigenetics. 2017 Dec;9(1):1-3.
[11] Choi HH, Cho YS, Choi JH, Kim HK, Kim SS, Chae HS. Stool-based miR-92a and miR-144* as noninvasive biomarkers for colorectal cancer screening. Oncology. 2019;97(3):173-9.
[12] Bastaminejad S, Taherikalani M, Ghanbari R, Akbari A, Shabab N, Saidijam M. Investigation of microRNA-21 expression levels in serum and stool as a potential non-invasive biomarker for diagnosis of colorectal cancer. Iranian biomedical journal. 2017 Mar;21(2):106.
[13] Knudsen AB, Zauber AG, Rutter CM, Naber SK, Doria-Rose VP, Pabiniak C, Johanson C, Fischer SE, Lansdorp-Vogelaar I, Kuntz KM. Estimation of benefits, burden, and harms of colorectal cancer screening strategies: modeling study for the US Preventive Services Task Force. Jama. 2016 Jun 21;315(23):2595-609.
[14] Knudsen AB, Rutter CM, Peterse EF, Lietz AP, Seguin CL, Meester RG, Perdue LA, Lin JS, Siegel RL, Doria-Rose VP, Feuer EJ. Colorectal cancer screening: an updated modeling study for the US Preventive Services Task Force. Jama. 2021 May 18;325(19):1998-2011.
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