Team:UPF Barcelona/Implementation

As for the implementation, our team had to envision Hormonic on the real world, making sure to make a safe feasible device. A rigorous study of who could be benefited the most from the device was performed. Finally, as a medical device, in order to be implemented, Hormonic needed to be classified according to the regulation in the European Union.

IMPLEMENTATION

• Prototype
  • Design
  • Safety & security
  • Pre-clinical studies
  • Post-clinical studies
• Potential users and beneficiaries
• Regulation of Hormonic
• References

Hormonic Prototype

Design

So far, we have seen how our team has come up with an innovative way to tackle hypothyroidism taking into account the whole physiological system. But let’s take a step further and try to picture how Hormonic could be implemented in a near future. Hormonic’s final prototype is intended to be an external device, placed on the surface of the skin in the back of the arm, setted with a microneedle array [1] that reaches the interstitial liquid in order to take samples by the use of suctioning pumps. It is also intended to have an app that has complementary information.

Figure 1. Design of Hormonic prototype

Once the sample is taken into an isolated compartment, where T3 meets our intein cell free sensor, the fluorescence expressed by the sGFP is measured by the photodiode. Then, this information is encrypted and sent to a computer that remotely regulates the administration of levothyroxine through a PID controller. The pharmac is injected by the use microneedles, which finally close the feedback loop.

Safety & security

Regarding the biosafety, in order to minimize the risk of the patient, experts have suggested to reconsider the insertion of living bacteria and replace these cultures by cell-free systems, thus reducing the environmental and infection related risks. Being formed by a cell-free system and a repository of Levothyroxine, the life-span of the device would be limited. However, since it is an external device, it is possible to refill the device, without having to discard the whole structure, reducing trauma that would result from a second insertion.

More on the computational security aspects related to the wireless communication between the device and the controller, specialists recommended the implementation of a symmetric-key algorithm within the very own device, which makes use of cryptographic keys for the encryption of the incoming and outgoing data and the decryption of that same information. In particular, they emphasized the high compatibility and good performance of the Advanced Encryption Standards (AES) 256. However, in order to prevent external agents from injecting data, digital signatures have proven to be useful, at the cost of a higher computational load.

Pre-clinical studies

Several aspects must be taken into account before carrying out the final implementation. As explained at our interview with experts such as Carles Zafon, from the SEEN association, the successfully engineered intein-mediated biosensor could be used to characterize the currently unknown metabolization of T4 into T3 and the circadian rhythm of T3. This knowledge would not only be useful for our correct implementation of the PID control system, but would be very valuable for the whole scientific community that works on this topic.

Beyond the studies that can help determine the technical aspects of the device, its use must be put in context before being released into the clinical world. As declared at the article that contains the joint statement of the European Thyroid Association (ETA) and Thyroid Federation International (TFI) [2], changes within the prescribed levothyroxine treatment have shown a marked increase in the number of side effects. Therefore, a bioequivalence test has been developed together with the ETA in order to establish compatibility between Hormonic and current treatments.

See bioequivalence tests

Furthermore, in order to meet the pharmac’s potency specifications, analisis over the stability of the levothyroxine solution must be carried out. This way the period of validity (time required for the 10% of the active component to be degraded) can be determined, as well as the instabilities related to temperature and pH.

Bioequivalence tests

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After reviewing the standards of levothyroxine bioequivalence defined by both the FDA and European protocols [3], due to the differences related to the drug administration mechanisms (tablet vs injection), we concluded that we were missing the reference to which we must compare the Area Under the Curve (AUC) and the Maximum Concentration (MC). Therefore, we decided that the bioequivalence test should be carried out the following way: monitor T4 concentration (ng/ml) every two hours during three days and check if it stays within physiological ranges. On top of that, we believe that once the adequate testing is found, correcting for the baseline contribution of the patient should not be an issue, a variable that is not taken into account in various current used bioequivalence tests.

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Post-clinical studies

Regarding the monitoring plan, patients that receive this new preparation would be retested with a serum TSH within 2-3 weeks in order to meet the joint demand of the American Thyroid Association, The Endocrine Society, and American Association of Clinical Endocrinologists. A complementary online questionnaire would also be sent [4].

Potential users and beneficiaries

In general, due to the large prevalence of hypothyroidism patients, the number of potential users is quite large: 10% of Spaniards and 5% of the general population. Most of them are prescribed levothyroxine tablets but around 40% of the patients do not follow their treatment properly and 30% of them keep showing symptoms in spite of being under treatment. Moreover, the range at which the drug is effective without causing adverse effects is quite narrow. Therefore, the benefits that can result from implementing Hormonic as an external device that rigorously controls hormonal levels are clear. Nonetheless, there are several subgroups within the hypothyroidism patient’s community that could really benefit from our device:

COVID-19 context

exhibit symptomes

Malabsorption

Pregnant people

Other disorders

Category within the COVID-19 context

According to the survey carried out by the Spanish Endocrinology and Nutrition Association (SEEN), the percentage of members that made use of the Teleconsultation service increased dramatically from 19,5% to 77,4% during the weeks of the pandemic [3]. Due to the chronic non-severe character of the hypothyroidism patients, most of their appointments and analytics were canceled, resulting in one of the most affected communities. However, the complementary physical explorations done to these patients are not crucial for their examinations, making them the perfect candidate for Telemedicine: a non-face-to-face care model for which Hormonic would be an essential tool. On top of that, we could identify several other subgroups such as those of risk that should avoid going to the hospital, people with low technological knowledge that can have trouble when connecting to a videoconference or even people with communication, linguistic comprehension, sensorial or intellectual disorders, who cannot easily describe their situation.

Patients that still exhibit symptomes

Around 10-20% of patients that are under current treatments, even if they show normal hormonal levels, still exhibit symptoms related to hypothyroidism. Although these patients have been prescribed T3 together with T4, arguing that their abnormal conversion of T4 to T3 is responsible for the adverse effects, clear improvements have not been reported. Hormonic could be used to pursue clinical studies in which irregular T3 level recordings could be carried out, together with the identification of the hypothetical abnormal conversion and the determination of whether the levothyroxine injection outperformed oral dosis.

Malabsorption

Hypothyroidism patients that suffer from this disorder are characterized by a reduced absorption capacity, which prevents them from getting all the levothyroxine that they require when administered orally. As a consequence, these patients must weekly go to the hospital in order to get a drastically painful intramuscular injection. Hormonic could help ease the pain generated by this administration technique, since subcutaneous injection of levohtyroxine has shown a rapid improvement with regard to clinical symptoms and thyroid hormone’s analytical data [5].

Pregnant people

The hormonal levels vary considerably during pregnancy from the first to the third trimester. If it is proved that the hormone transfer to the fetus does not affect its viability, this subcategory could be one of the most benefited, since it would have its hormonal levels controlled.

Other disorders related to the thyroid hormones

The general mechanism used by Hormonic could be redirected as to administer antithyroid drugs to hyperthyroidism patients and counteract its overproduction of hormones; or administer levothyroxine to patients with thyroid cancer in order to maintain TSH levels low and prevent it from activating tumoral cells, while ensuring the lowest possible level of hyperthyroidism.

Regulation of Hormonic according to EU

The intended use of Hormonic is to artificially regulate thyroid hormone levels. To do so, the device contains a biosensor, a reservoir of levothyroxine and microneedles to reach the interstitial fluid. According to this intended use, Hormonic is classified as a medical device.

Legislation to be applied

Nowadays, two different leslations are in force: directive 93/42/CEE of medical devices and 2017/745. However, since the directive 93/42/CEE will be derogated by 26th of may of 2021, we based the classification of our product based on the Regulation (EU) 2017/745 of the European Parliament and of the Council of April 2017 [6].

Definition of the medical device

Based on the current European regulation, the Hormonic prototype would correspond to a medical device because its medical purpose could covers diagnosis, monitoring and treatment of a disease.

Click to see the formal definition
of a medical device

Medical Device definition

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From the current legislation[6], the definition of medical device is the following:

‘Medical device’ means any instrument, apparatus, appliance, software, implant, reagent, material or other article intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the following specific medical purposes:

• Diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of disease.
• Diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or disability.
• Investigation, replacement or modification of the anatomy or of a physiological or pathological process or state.
• Providing information by means of in vitro examination of specimens derived from the human body, including organ, blood and tissue donations.

and which does not achieve its principal intended action by pharmacological, immunological or metabolic means, in or on the human body, but which may be assisted in its function by such means.

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Classification

Once it is clear that our product is a medical device, before it can be commercialized, we must identify its classification, since the requirements may vary. According to the annex VIII of the Regulation (EU) 2017/745 [6], Hormonic would correspond to a long term invasive device, since it is intended to be more than 30 days on the body and it penetrates inside of the body not through a body orifice.

Based on the Rule 8 (found in chapter III from annex VIII, paragraph VI) of the mentioned regulation [6], all implantable devices and long-term surgically invasive devices are classified as class IIb, unless they are intended to administer medicinal products, in which case they are classified as class III. Therefore, Hormonic T3 biosensor device corresponds to class III [6].

Click here to see medical device
classification related definitions

Medical Device classification related definitions

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Classification based on the duration of use:

• Transient: means normally intended for continuous use for less than 60 minutes.
• Short term: means normally intended for continuous use for between 60 minutes and 30 days.
• Long term: means normally intended for continuous use for more than 30 days.

Invasive and active devices definition:

‘Surgically invasive device’ means:
(a) an invasive device which penetrates inside the body through the surface of the body, including through mucous membranes of body orifices with the aid or in the context of a surgical operation; and
(b) a device which produces penetration other than through a body orifice.

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Which are the requirements to commercialize Hormonic?

According to 2017/745 Regulation [6], medical devices are submitted to CE marking in order to be placed on the market. For class III devices, this CE marking needs to be granted by a notified body. The notified body is responsible of the evaluation of the product and, if agreed, it will emit a certificate of the CE marking to the manufacturer authorizing they to place the CE marking on the product.

References

[1] Ronen Polsky, Philip Rocco Miller, Justin T. Baca In vivo extraction of interstitial fluid using hollow microneedles. Patent WO/2016/164208 2016

[2] Fliers, E., Demeneix, B., Bhaseen, A., & Brix, T. European Thyroid Association (ETA) and Thyroid Federation International (TFI) Joint Position Statement on the Interchangeability of Levothyroxine Products in EU Countries European Thyroid Journal, 7(5),2018, 238-242. doi: 10.1159/000493123

[3] Gottwald-Hostalek, U., Uhl, W., Wolna, P., & Kahaly, G. New levothyroxine formulation meeting 95–105% specification over the whole shelf-life: results from two pharmacokinetic trials. Current Medical Research And Opinion, 33(2), , 2016, 169-174. doi: 10.1080/03007995.2016.1246434

[4] Gorgojo Martínez, J., Zugasti Murillo, A., Rubio Herrera, M. and Bretón Lesmes, I.TELECONSULTA En Endocrinología Y Nutrición En Tiempos De La Pandemia COVID-19 Y Más Allá Seen.es., 2020,vailable at: [Accessed 22 October 2020].

[5] Groener, J. B., Lehnhoff, D., Piel, D., Nawroth, P. P., Schanz, J., & Rudofsky, G. Subcutaneous application of levothyroxine as successful treatment option in a patient with malabsorption. The American journal of case reports, 14, 2013, 48–51. https://doi.org/10.12659/AJCR.883788

[6] Regulation (EU) 2017/745 of the European Parliament and of the Council of April 2017, Official Journal of the European Union

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