FMT harmonized regulations are lacking and the current regulatory status ranges from non-existing to strictly regulated (22). For now, the US FDA had classified FMT as a live biotherapeutic drug that requires the submission of Investigational New Drug application for its therapeutic uses (23). CDI has been recently exempted from IND application filing, which was a decision received with high appreciation by clinicians to use FMT in a fatal ailment. Meanwhile, strict regulation and control over the use of such treatment was recommended by, Renzong Qiu, 2017 (24). He reported a concern over FMT misuse similar to stem cell treatment scenario which lately had led to a scandal in China. At that time, stem cell therapy was misused and was considered as a panacea for a multitude of clinical conditions without solid scientific evidence (24). These two different regulatory perspectives, Western versus Chinese, highlight how cross cultural differences can influence the shaping process of FMT regulations. Still, there is a gap in the understanding of FMT around the world. A study among the patients who are admitted to gastroenterology clinics in urban hospitals in California (USA) found that only 12% had knowledge what FMT is although they were receptive to the procedure itself, especially among those with college degrees (25). Interestingly, medical students attending various leading medical institution in China, also had low recognition level of FMT, that is around 48% of them did not know what FMT is (26). Accordingly, we expect that Jordan's specific social norms, tradition, customs and religion backgrounds and structures would have an impact on the attitude towards introducing and regulating FMT (24).
Our results demonstrated that the majority of the respondents heard of FMT treatment but did not practice it. In contrast to Jordan where FMT is not regulated nor practiced yet, FMT has been practiced in China since the fourth century where the traditional Chinese medicine used yellow soup, fecal slurry, orally to treat food poisoning and diarrhea (14, 27). This justifies the high familiarity of this treatment modality among Chinese clinician (14). Nevertheless, the familiarity does not guarantee experience in using it by clinicians; Zipursky, et al. (28) in their study reported that physicians have limited experience with FMT despite having treated patients with multiple recurrent CDIs.
In general, our study population were not enthusiastic about nor supportive of the introduction of such treatment. They did not see its promising utility for other future applications. Barriers towards the promotion and recommendation of FMT include mostly the absence of official guidelines and regulations followed by the risk of infections and long term risk and safety. This is in concordance with Kelly et al.(29) presentation of physicians attitudes towards FMT in 2010 at the American College of Gastroenterologist meeting. In that presentation, 40% of physicians who had heard of FMT, were not willing to try it, pending further demonstration of its efficacy safety. Nevertheless, Kelly et al., showed that physicians’ recommendation was positively influenced by patients' perceived acceptance (29, 30). This was not what our respondents think. In general, unwillingness for recommending FMT treatment were previously related to many factors; the limited knowledge among the study population (31), the limited practicing numbers (32) and the “yuck”factor (33). Other reasons for physicians not offering or referring a patient for FMT were; "not having the right clinical situation’, "the belief that patients would find it too unappealing", and "institutional or logistical barriers" (28). In his commentary, Brandt et al., (33) related physicians' hesitation to recommend FMT to the limited randomized controlled trials to show effectiveness and safety. He predicted that patients' needs in addition to the availability of formulations that are aesthetically acceptable are influential parameters towards the acceptance of this treatment modality among physicians. Indeed, we reported the lower part of GI as the only acceptable route of administration of FMT. This might affect how the accepted FMT formulation to be in introduced and regulated in Jordan in the future.
In support of the international legislations, our respondents will not recommend FMT as a first line treatment, but only recommend when there is failure of conventional treatment or they want organic natural treatments. This is in agreement with the Iranian clinicians and gastroenterologists attitudes who reported a willingness of accepting FMT as a therapeutic option if it is scientifically justified and ethically approved given it was used as synthetic microbiota rather than FM (34).
Clinical efficacy is a crucial factor that maintains patients’ positive attitudes towards fecal microbiota transplantation (35) and physicians advising and referring patients to FMT treatment modality. The reported physicians’ responses regarding the efficacy and safety of FMT were diverse. While a major concern about FMT efficacy and safety was reported among Chinese clinicians (Ma, 2017), Zipursky et al., (28) have reported minor doubts about FMT's efficacy and safety among physician respondents at Dartmouth-Hitchcock Medical Center and Baylor College of Medicine (Texas, USA).
In light of the above described barriers and limited efforts in increasing the awareness of the uses and efficacy and safety of FMT treatment modality, we predict that the introduction and the regulation of this treatment modality in Jordan is not soon.
According to the US FDA, during the investigational use of FMT, the potential risks and benefits including the unknown risks and the long-term risks should be clarified for qualified patients during the consenting procedure (Food and Drug Administration 2013). Consenting is an ethical challenge in FMT, which was recognized by close to 50% of our participants. The FMT consenting procedure should consider patients' vulnerability, unforeseen long term risks and limited knowledge of the actual benefits and risks to the treatment in addition to the universal ethical requirement of biomedical research (36) . Ma et al., (2017) [13] believe patients' compromised decision making capacity and vulnerability are the main challenges to informed consent. They consider CDI patients vulnerable, and desperate individuals who can be easily affected by emotive language as being natural and safe whether from physicians or the media. This was opposed by Bunnik et al., 2017(9) who believe that it is not the vulnerability or capacity to consent but rather the inadequate information that poses difficulties with regards to the FMT consenting procedure. The quality of adverse effects and risks anticipated when performing FMT is a challenging dimension in FMT procedure. Some of these are actual, as shown in the last report of FDA, (36) and others are predicted with no strong evidence, or, only examined in preclinical (i.e., animal) studies (Bunnik et al., 2017) (9). Moreover, a new risk related to the current COVID-19 pandemic has been recognized, where the international group of experts in faecal microbiota transplantation and stool banking recently proposed the addition of SARS-CoV-2 to the current FMT donor screening measures (37). Bunnik et al., 2017 (9) highlighted that the risks of FMT may be underestimated by clinicians who are not familiar with preclinical studies. While agreeing that desperation should not be the basis for treatment decision, he demands that physicians should discuss potential long-term risks of FMT to ensure informed consent. This was appreciated by the physicians in Ma study where the majority (71% of all 100 respondents) reported they would inform patients of all known and possible risks (physical, mental, cognitive, and behavioral) and let them decide. A portion of our respondents reported that they will provide patients with all anticipated risk (44%) while 37.7% will take into consideration the comprehension capacity of the patients. This lower percentage supporting informed consent is related to poor training in ethically informed consent for clinical or research and experimental purposes.
In addition to anticipated risk, other important challenging parameters in the consenting process was highlighted by Cohen & Vardit Ravitsky (2017) (20). These were the cultural/religious or personal/ideological food restrictions (Ya'arit Bokek) of stranger donor. In their commentary, they questioned whether informed consent to FMT can be obtained without information about the donor’s diet. This might be very relevant in our region. In that population of Jordan, that is mostly Muslim, observing the religious commitment to halal nonalcoholic containing foods and beverages is essential. Our respondents think that religion, dietary and alcoholic consumption will be considered as a barrier in patient's acceptance to FMT procedure. Accordingly, we perceive that it could be necessary to declare the donor’s dietary habits to obtain an autonomous decision in this region.
An important parameter that was highlighted by the respondent's comments was the need to consider the religious point of view and to seek Fatwa. This was declared by 30% of the participants in addition to their perception of the need for more knowledge about safety. Therefore, we concluded that our health care practitioners are reluctant to use the FMT modality because of concerns about safety and religious beliefs (14).
Although, there is a growing awareness of ethics in human research, nevertheless Alahmad et al., 2012 have shown that research ethics regulations and guidelines in Middle Eastern Arab countries suffer from various degrees of deficiencies with regards to ethical protection (38). They recommended that social norms, tradition, customs and familial ties should all be taken into consideration when developing policies and regulations. In Interviews with medical professionals from the Middle East Alahmad et al., 2015 (39) reported the social importance of protecting confidentiality, de-identification and anonymity of donors scored 100% as being an ethical concern in conducting FMT among the Jordanian clinicians. They mostly agreed that confidentiality can be protected by double blinding both the donor and the receiver in addition to ensure the confidentiality of patient information during communication with others.
In conclusion, our study demonstrated lack of enthusiasm to implement FMT in Jordan although there is general support for its potential as a second line of treatment when traditional medical treatment fails. There are complex ethical, religious, and practice based challenges that needs to be addressed before FMT becomes an established practice. Future studies should examine FMT from local traditional and especially religious perspectives as well as other barriers found in our study, as well as others (consenting, privacy, risks.). Patient (end-user) perspectives are lacking and would be important to understand the level of acceptability among those who need FMT. Furthermore, there should be more education to increase the understanding of FMT benefits and risks among Jordanian health care practitioners.