I want to commend to you the guest editorial by Dr Ramin Parsa-Parsi and his colleagues on the 2013 revision of the World Medical Association”s (WMA”s) Declaration of Helsinki.1 This seminal document has been revised over the years, in keeping with the increasing sophistication of the field of bioethics as well as the expanding responsibilities for global health and international medicine. Dr. Parsa-Parsi headed the revision committee of the WMA for this latest revision, an extremely important position and task. We have just welcomed him as a new member of the international editorial board of the Southern Medical Journal, a great honor for our publication. The authors of this editorial identify the Declaration of Helsinki as a “living document, one which was born in 1947, a time of great challenge for the medical profession and its integrity in patient care and human research. Following World War II, a number of Nazi physicians were placed on trial—a total of 12 trials—in Nuremberg, Germany for war crimes and atrocities, including human experimentation and genocide, committed against human beings. These were known collectively as the Nuremberg doctors” trials, and included Adolf Hitler”s personal physician and the chief physicians of several of the Nazi concentration camps. As the conduct of unethical experimentation on people by Nazi physicians became known globally through testimony and evidence, there was a realization of certainty within the international medical community that clear and concrete regulations for the conduct of legitimate human research must be developed and adhered to. Also clear was the realization that Nazi physicians had philosophically and functionally uncoupled the important dyadic principles of beneficence and nonmaleficence, effectively discarding or ignoring the enduring Hippocratic principle of “first, do no harm. While the Nuremberg trials were progressing, the Nuremberg Code was developed—a list of 10 guiding principles for the proper and ethical conduct of human research. Although never translated into law, the Code became the philosophical foundation for the more globally recognized regulations for human research compiled in the original 1947 Declaration of Helsinki. In fact, it is my understanding that the WMA was born as a result of the global medical profession”s recognition that a powerful voice for ethics and integrity needed to be heard. In addition, the WMA developed the Declaration of Geneva, which has become a widely used and highly regarded alternative to the Hippocratic Oath for delineating the obligations and duties of a physician. Every healthcare provider should be familiar with the Declaration of Geneva and the Declaration of Helsinki, as well as the fundamentals of human research obligations defined in the original Nuremberg Code. The principles codified in the Declaration of Helsinki became the basis for the regulations defining human subject research subsequently adopted in the United States. It is at once fascinating and appropriate that this document has been revised through the decades to reflect the modern practices of medicine and medical research, which confirms the importance of its principles to the advancement of science and the protection of human research subjects. We thank Dr Parsa-Parsi and his colleagues for their dedicated effort in this regard and for helping us better understand this vitally important document and its enduring application to modern medicine.
Key Points Compounding pharmacies are important for patients who have medical conditions such as vulvodynia that have few, if any, commercially available treatments. Congressional efforts to tighten regulations on compounding pharmacies, although necessary, will undoubtedly affect health care, with a potentially profound impact on women”s health issues. For better patient outcomes from medications prescribed to a compounding pharmacy, we believe proper communication between the doctor and pharmacist and the pharmacist and patient is essential to ensure medications are compounded in the most effective manner as possible. Compounding pharmacies have come under much scrutiny following the fungal meningitis outbreak caused by preservative-free methylprednisolone linked to the New England Compounding Center in Framingham, Massachusetts.1 As of February 4, 2013, the Centers for Disease Control and Prevention reported 696 cases of fungal meningitis across 20 states, resulting in 45 deaths (the initial outbreak occurred in 2012).2 As a result of this tragedy, the Verifying Authority and Legality in Drug Compounding Act was introduced in Congress in November 2012.1 The purpose of this act is to give the US Food and Drug Administration the necessary authority to oversee compounding pharmacy practices across the country.1 Unfortunately, the 2012–2013 outbreak is not the only incidence of patient harm caused by compounded preparations during the last decade nor was the 2012 compounding act the only legislation proposed to implement stricter regulation of compounding pharmacy practices. In 2007, the Safe Drug Compounding Act was introduced in an attempt to provide the Food and Drug Administration with tighter regulatory control over compounding pharmacies and the medications compounded.3 Although in some respects necessary, tighter governance of compounding pharmacy practices has the potential to adversely affect advances in novel therapeutics and compromise patient care.4 One patient-specific population likely to be negatively or positively affected by the aforementioned legislation is women with vulvovaginal conditions such as vulvodynia. With limited commercially available therapies, patients and clinicians alike routinely refer to compounding pharmacies for treatment options. Despite a population prevalence of approximately 15%, vulvodynia remains an elusive disorder characterized by chronic vulvar burning, stinging, rawness, soreness, or pain in the absence of objective clinical or laboratory explanations.5 Vulvodynia and related pain disorders may be considered a “pseudo-orphan disease, which is a condition that is “not adopted by the pharmaceutical industry because it provides little financial incentive for the private sector to make and market new medications to treat or prevent it.6 Alternatively, according to US criteria, a rare disease, one that affects fewer than 200,000 people, can be given orphan status. Clearly, vulvodynia is not a rare condition because it affects approximately 1 in 10 women at some point in life. In addition, it is not feasible to obtain pharmaceutical investment in research and development because the condition is deemed etiologically heterogeneous with considerable controversy on nomenclature and treatment.7 Vulvodynia has received increasing attention by both the medical profession and media, and more women are aggressively seeking care.5 No standard treatment exists, however, leaving many women and their treating physicians to rely on compounded medications and word of mouth to control the symptoms of this complex condition. The extent to which the compounded formula is based on rational pharmacological principles with potential or definite benefit (eg, Bendectin, combination of doxylamine succinate and pyridoxine hydrochloride, for treatment of nausea during pregnancy8) versus an expensive and potentially ineffective venture for the desperate or misinformed patient is unknown. Our hypothesis was that compounding for women”s health constitutes a significant portion of compounding pharmacies” practice. Focusing on vulvodynia, we further sought to characterize common indications and specific formulations dispensed by compounding pharmacies. Methods We identified all registered pharmacies (n = 2304) across North Carolina by contacting the North Carolina Board of Pharmacy. After excluding chain pharmacies (44%, n = 1020), we attempted to ascertain whether the remaining nonchain pharmacies (56%, n = 1284) compounded medications for human use. After three attempts at contacting nonchain pharmacies, we were unable to determine the compounding status for 127 pharmacies (10%), 114 pharmacies could not be reached, and 13 pharmacies refused to participate. Of the remaining 1157 nonchain pharmacies contacted, 504 (44%) pharmacies indicated that they did not compound medications for human use; therefore, our cohort consisted of 653 (56%) registered pharmacies in North Carolina that compounded medications for human use (Fig.). Fig Disposition of responders. We administered a 19-item online questionnaire to assess demographics, practice patterns, common compounding indications, and types of medications compounded. This 19-item questionnaire, focusing on compounding practices surrounding women”s health and, more specifically, vulvodynia, was developed in consultation with the survey methodology team at the University of North Carolina Social Sciences Research Center (Odum Institute). We did not offer an incentive for participating in this study; however, to increase the response rate, we sent e-mail or postal reminders, depending on a respective pharmacy”s preference. Up to three reminders were mailed 8 to 10 weeks apart during the study period. With each reminder, individual pharmacies were provided with their unique four-digit identification code along with detailed instructions on accessing the online survey. Skip patterns were used in the survey. For example, if the pharmacists entered 0 for the percentage of compounded medications dispensed on average per day for human, adult, or women”s health, they were directed to the end of the survey. This strategy was used to limit responses from pharmacies that did not meet the qualifications for study participation. Results The daily prescription volume for commercially available medications was normally distributed in our cohort. The 200 pharmacies that responded to our survey represented an unskewed geographic distribution across the state of North Carolina. Of the 200 respondents, 75 pharmacies filled 101 to 200 (38%) prescriptions per day. Forty-five pharmacies (22%) and 35 pharmacies (18%) dispensed 201 to 300 and 300 prescriptions per day. Data were missing for 11 pharmacies (5%). The majority of pharmacies (79%, n = 149) compounded medications for both adults and children and 21% (n = 40) compounded for adults only. Of the 195 pharmacies reporting the number of prescriptions compounded per day, the majority (90%, n = 175) filled 51 medications on average per day. Three common reasons for compounding medications were combination of medications not commercially available (44%, n = 86), drug not commercially available (24%, n = 46), and dosage form not commercially available (22%, n = 43). Furthermore, reflecting on the 30 days preceding the survey, the most common indications for compounding medications represented as an average percent were otolaryngological applications (eg, magic mouthwash, nasal irrigations) (30%), dermatological preparations excluding vulvovaginal preparations (28%), and women”s health issues (eg, vulvovaginal pain, vaginal infection, vaginal dryness, sexual dysfunction, bioidentical hormone therapy) (19%). Eighty-six of the pharmacies surveyed reported dispensing compounded medications for women”s health issues. Among the 86 pharmacies, 73% (n = 63) reported compounding for bioidentical hormone therapy, 70% (n = 60) for vaginal dryness, 65% (n = 56) for low libido, 29% (n = 25) for vulvar pain, 27% (n = 23) for other health issues, and 16% (n = 14) for vulvovaginal infections. (Respondents could report compounding for multiple indications, thus allowing the percent sum to exceed 100%.) Among the 25 respondents who reported compounding medications for vulvar pain during the previous 30 days, most (92%, n = 23) reported that of the total number of prescriptions compounded for women”s health, <25% were for the indication of vulvar pain. The top five frequently occurring medications used at least once during the preceding 12 months in compounding preparations for vulvar pain were lidocaine (60%, n = 15), estradiol (52%, n = 13), estriol (52%, n = 13), testosterone (52%, n = 13), and progesterone (44%, n = 11). Respondents also were queried on the different strengths of estradiol they used in compounded preparations for vulvar pain in the preceding 12 months. Among the 13 respondents who reported compounding with estradiol, the strength most often used was 0.01% (85%, n = 11), followed by 0.02% (54%, n = 7), 0.025% and 0.03% (both at 31%, n = 4). The most common combination of medications compounded for vulvar pain was estradiol, lidocaine, and testosterone; however, there was considerable variation in the combinations used. On average two, but as many as four medications, were compounded in preparations for vulvar pain. In addition, the two most common bases used in compounded preparations for vulvar pain were emollient cream (40%, n = 10) and petrolatum (36%, n = 9). Compared with pharmacies that reported having no pharmacists with special training in compounding medications (65%, n = 130), pharmacies reporting having at least one or more pharmacists with special training (35%, n = 70), on average, filled a greater percentage of prescriptions for compounded medications specifically for women”s health issues in the 30 days preceding the survey (5% vs 41%, respectively), and this difference was statistically significant (t(91) = −9, P < 0.001). When asked about the specific categories of medications compounded within the previous 30 days, the 70 pharmacies reporting one or more pharmacists with special training in compounding medications reported the following four reasons for compounding: women”s health issues (41%), dermatological conditions (18%), otolaryngological conditions (14%), and pain management (9%). Discussion Compounding pharmacies play a pivotal role in meeting the unique needs of patients and providers. In many situations, patients and providers turn to compounding pharmacies as a last resort to treat medical conditions. In some conditions, compounded medications are simply a different formulation (eg, suppository vs oral suspension) of an already-effective therapy with well-characterized pharmacokinetics and dosing. In other instances, however, compounded medications serve as the final effort in treating conditions with no known standard of treatment; alleviating vulvovaginal complaints often falls into this category. Legislative attempts to tighten governmental control of compounding pharmacies without a contextual assessment of the role of compounding pharmacies in patient care will not be sufficient to meet the intended objective of quality assurance in dispensing practices. Scientific merit aside, women view compounded formulations as “safe, with fewer side effects and are equally or more effective for symptom management.9 Development of guidelines and standards in dispensing practices will serve to ensure the safety in patient care and practitioners, and although such a practice has long been endorsed and implemented in some areas of compounding practices, no such recommendations have been established in compounding formulations in women”s health.10 Although a study targeted independent community pharmacies in Illinois, Missouri, Kansas, and Iowa,11 to our knowledge ours is the first statewide survey in North Carolina to focus on compounding practices with a special focus on women”s health, specifically vulvodynia. One limitation of our study that should be noted was the poor response rate of 30%, likely meaning that our respondents are not universally representative. We believe that the respondent pharmacies are more conscientious, thus representing the “cream of the crop of compounding pharmacies. We are unable to comment about the direction of bias in our results; however, our findings were consistent with the study”s clinical observation. Nevertheless, it is curious that a high percentage of compounded medications were for the indications of hormonal therapy and vaginal dryness, areas in which there are a number of commercially available alternatives. Another interesting result was the most common base used to compound medications for vulvar pain, emollient cream. When referring to the vulvar region, a wet mucosal surface, a sticky base (eg, hydrophilic petrolatum) would be the best delivery vehicle; therefore, use of emollient cream could lead to decreased absorption of medications and ultimately decreased efficacy. The obvious question is why would compounding pharmacies use a suboptimal base? On the surface the answer seems simple—lack of communication among physicians, pharmacists, and patients; however, in reality, this lack of communication is an immense and complex problem that is compromising patient care.10 Often when physicians write prescriptions, they do not include a medical indication on the prescription. In many situations, the pharmacist does not ask the patient details about the prescription before compounding, and therefore the pharmacist compounds the medication in the most common base. To address these deficiencies, practice standards for compounding preparations such as those that exist for the standard preparation for total parenteral nutrition are necessary. Based on our experience in this study, we believe that such standards should include but not be limited to the medication indication, area of application (mucosal surface vs nonmucosal surface), doctor-to-pharmacist communication to ensure complete understanding of medication usage, and pharmacist-to-patient communication before compounding the medication to ensure that the medication is compounded in the most effective manner as possible for the individual patient. Matheny and Martin discussed the vital role that compounding pharmacies play in providing medications not commercially available, and included questions that patients should ask their compounding pharmacist regarding the compounding facility and quality of medication.12 We want to conduct a follow-up survey focused on vulvodynia, but narrow our compounding pharmacy participants. Specifically, we want to focus on those compounding pharmacies that meet both criteria of only compound medications (ie, do not dispense commercially available medications) and at least one pharmacist who has special training in compounding medications. It is our belief that such compounding pharmacies would produce different responses that demonstrate more efficacious patient care. Conclusions Compounding pharmacies play a critical role in compounding medications that are not commercially available for disorders such as vulvodynia without consensus treatment. Women”s health issues are the third leading reason for compounding medications, with 13% (n = 25) of pharmacies compounding medications for vulvar pain. Given both the lack of commercially available medications and consensus guidelines for the treatment of vulvodynia, our results provide critical knowledge about conventional medical practices. Focusing on the larger landscape of women”s health, it is unfortunate that scientifically proven and effective formulations, such as Bendectin, which irrefutably improves the nausea and vomiting associated with pregnancy, are not the cornerstone of compounding practice. Conversely, low libido, which has limited data on mechanisms of action and treatment efficacy, is the third most common indication for compounding. Based on our study, it seems that we do not completely use the power of compounding pharmacies to address the unmet needs of millions of women.
Key Points Cervical cancer disproportionally affects women from racial/ethnic minorities in the United States as a result primarily of lower screening rates when compared with non-Hispanic whites. Self-sampling for human papillomavirus infection in which women collect their own cervicovaginal samples has the potential to circumvent barriers (eg, embarrassment about the pelvic examination) to regular screenings with a Papanicolaou test. The main concerns of using self-sampling as an alternative to the Papanicolaou test were concerns regarding the accuracy of the test and concerns about performing the test correctly. Decreasing incidences of cervical cancer in developed countries have been attributed to the introduction of screening via cervical cytology either with conventional Papanicolaou testing or with liquid-based cytology to detect preinvasive cancer.1 (In this article, we refer to either liquid-based cytology or the Papanicolaou test as Pap test, since this is how it is widely known.) In 2012, the US Preventive Services Task Force added cotesting for high-risk human papillomavirus (hrHPV) for cervical cancer screening.2,3 A novel method for hrHPV testing is self-sampling, in which women collect their own cervicovaginal samples. Studies have found high sensitivity (70%–90%) and high specificity (80%–88%) for hrHPV detection with self-sampling when using physician-collected samples as the gold standard.4–7 Although not recommended in the United States, an algorithm that proposes using hrHPV alone as the primary screening method for cervical cancer suggests that women who test positive for hrHPV during the initial screening may need a follow-up with cervical cytology. This would spare women at low risk (hrHPV negative) unnecessary cervical cytologies,8–10 potentially reducing costs. Hispanic women living along the US border with Mexico have one of the highest cervical cancer mortality rates in the nation, at 5.7 deaths per 100,000 population, compared with the national average of 2.4 deaths per 100,000 (age adjusted to the 2000 US standard population).11 This is, in part, the result of the lower cervical cancer screening rates of 72% of Hispanic women in the El Paso, Texas, area versus 81% of Hispanic women nationally.12 Factors contributing to this include lack of access to health care and fear of and embarrassment about the pelvic examination.13 These barriers could be circumvented by the use of self-sampling for hrHPV infection. Studies in developed countries have shown that women who did not attend regular cervical cancer screening programs were more likely to perform self-sampling than to undergo a Pap test for screening when both methods were offered.14–21 This likelihood extended to resource-poor populations in China and Mexico.22–24 Additional information is needed regarding the attitudes of Hispanic women toward self-sampling as an alternative to the Pap test for cervical cancer screening. Methods Population Studied Focus groups were conducted among a primarily Hispanic group of women living along the US–Mexico border to explore their knowledge, beliefs, and attitudes25 toward cervical cancer screening methods and self-sampling for hrHPV infection. Eligibility was determined based on the US Preventive Services Task Force criteria for hrHPV cotesting—women aged 30 to 65 years with an intact cervix. We excluded women with abnormal uterine bleeding, a history of cervical cancer, a history of hysterectomy, or if pregnant. Patients were recruited from two university-based family medicine clinics. Procedure The study was reviewed and approved by the institutional review board at Texas Tech University. Participants either self-referred to the study or were actively recruited from clinic waiting areas. We conducted a total of five focus groups, with three to six women in each group, expecting saturation to be reached with this size cohort.25 One focus group was conducted in English, three groups were conducted in Spanish, and one group was conducted in both Spanish and English. An experienced bilingual native Spanish speaker guided the discussion of each focus group and a bilingual native Spanish-speaking research associate served as the note taker; neither was certified in Spanish. During focus group sessions, personnel explained the study and consented subjects. Participants filled out demographic questionnaires before the beginning of the focus group interview/discussion. The focus group interview was conducted with the oversight of a focus group guide. Following discussions regarding knowledge, attitudes, and intentions for screening, familial and institutional support, and barriers to cervical cancer screening, participants were shown a self-sampling kit and were provided a brief description of the method of collection. Participants” attitudes toward self-sampling were then explored, with each session lasting between 2 and 2½ hours, with a $20 incentive given to the participants. Statistical Analysis The theoretical framework for the focus group”s guide was the health belief model, using the constructs of perceived susceptibility, perceived barriers and perceived benefits to present screening methods, and perceived barriers and benefits to using self-sampling. We recorded each focus group interview using two iPads located in the room. A bilingual note taker served as a backup location in the room. The recordings were transcribed verbatim into a Microsoft Word document in the language of the focus group. The Spanish and bilingual transcripts were then translated into English by native Spanish-speaking bilingual research personnel experienced with translations. Transcripts were reviewed for obvious errors by the principal investigator, who was also a native Spanish speaker and bilingual. Disagreements were resolved by consensus among research personnel and the principal investigator. The final transcriptions were uploaded into NVivo version 10 qualitative data analysis software (QSR International, Burlington, MA) for thematic analysis of the focus groups. We identified a priori themes from the focus group”s guide and used a group coding approach. We iteratively added new themes as they emerged, using the constant comparison method until saturation was reached. We used deductive coding for the preidentified themes and inductive coding for the emerging themes.26 All of the investigators reached agreement, selected the list of quotes assigned to each theme, and discussed the range of responses. Results Demographics Of the 21 women attending the focus groups, 80.0% self-identified as Hispanic. The majority of the participants reported being born in Mexico (57%), 38% were born in the United States, and one participant was born in El Salvador. The mean age was 53.4 (range 37–65) years, with an average length of residence in the United States of 25.0 years. A total of 31.6% of the participants reported an annual household income of ≤ $10,000, whereas only 25.0% reported any form of post–high school education. Only one participant reported having private insurance, 28.5% had government insurance, and 66.7% had some form of discount, charity care program, or no healthcare coverage at all. Approximately half of the participants ranked their health as fair or poor, and 60% had a regular healthcare provider or physician. Most of the participants had heard of cervical cancer before participating in the trial (90.5%) and 38.1% had not had a Pap test in the last 3 years (Table). Table Characteristics of focus group participants (N = 21) Cervical Cancer Awareness and Knowledge Although many of the participants had heard of cervical cancer and were familiar with the availability of the Pap test for screening, most could not recite the risk factors for cervical cancer. Women did not mention the age at which a Pap test was recommended, nor did they mention the signs and symptoms of cervical cancer. One participant said, “I”m ignorant when it comes to this topic…I don”t know what causes this type of cancer … Well, in reality, I don”t know a lot about the disease. Many reported they believed that some type of infection led to cervical cancer, especially when these infections were not treated properly. Participants indicated that the infections ranged from sexually transmitted infections to infections that could be contracted from restrooms, beds, and poor general hygiene. One participant mentioned HPV as a possible cause of cervical cancer following comments by another participant that sexual intercourse with unclean, noncircumcised males could increase the risk for contracting cervical cancer. A participant said, “Hygiene, when you have intimacy, in either the man or woman. In one occasion, I hear on TV that when men don”t have the thing…how do you call it, the circumcision, they produce a bacteria … produces that the uterus accumulates this and other bacteria and in turn cancer occurs. I heard this for many years and that helped me because with my partner I always told him: If you are not clean then nothing won”t happen. Those are the things that I heard along with others. Another woman said, “Umm, like she said, they say the male is the carrier of HPV, ‘cuz I don”t know if that is the main cause of the cervical cancer, I don”t know, I meant I am not sure. There also were myriad anecdotal discussions on sexual exposure as a cause of cervical cancer, especially when people were exposed to multiple sexual partners. A participant said, “I am very old fashion, just like my mom; she used to tell me if you have two or even three partners, then you will get cancer. When it came to general awareness about cervical cancer, participants expressed concern that there was not much general information available about cervical cancer. Participants believed that they received a fair amount of information via the media about other conditions but did not hear much about cervical cancer. A participant said, “I don”t think [it] is so much your family members, is what you see on TV. Another woman said, “But if we have the information, because I watch TV and there is a lot of help for diabetes but not for cancer. Perceived Susceptibility Many of the participants indicated they believed that all women were at risk for cervical cancer; however, some of the participants believed that the risk was higher for women who had multiple sexual partners, for younger women, and for those who did not “take care of themselves. The theme of cervical cancer being a problem for women who had multiple sexual partners was repeated by several participants. One woman said, “People that have sexual relations with different partners without taking any precautions, without taking care of themselves. Another participant said, “Like the ‘women from the night” [sex workers], I think that they are more exposed because they deal with more men. Perceived Screening Method Barriers Participants mentioned pain associated with the Pap test as a barrier, “Yes, they always tell me since that time that happened to me, they did tell me, but it was painful. I bled. They didn”t know what to do, I wasn”t relaxed, although they had told me already what to expect but then I saw all those things and thought all of that is going to be inside me and then, well, they showed me how those things are used and how they are inserted inside me…and just like that.. Another woman said, “Yeah, whenever they do a Pap smear and they put that thing [speculum] it hurts. Some participants mentioned lack of effective communication with the physician: “It is really hard when you have to deal with doctors who do not want to provide you with any information and have a taciturn disposition. Some doctors stick to writing a note and won”t answer anything else even if you ask them and they leave you thinking what is going to happen because he didn”t tell me anything and they even get bother when you ask them. For the patients” peace of mind, they should give all the required information. Another woman said, “For them [doctors] to be specific, because sometimes you can”t understand the information the doctor gives you. One woman said, “I think that besides that they don”t give you the results on time, I would like for the doctors to explain to me more any evidence of how this type of cancer evolves. Information besides the test. One participant mentioned distance to the clinics and problems with child care as barriers: “They should have more clinics available because sometimes the ones available are very far away. There are people that work or have a family to take care of or I don”t know…They have to find someone to take care of their babies or maybe ask permission at work, or sometimes the distance takes away half the time you have available. All of those things are very important to receive help. Screening Facilitators Participants expressed that they would like to have a choice of different methods to screen for cervical cancer, such as a blood test that would make screening much easier. Characteristics that emerged as important to this group were ease of testing, accuracy, and cost. When discussing accuracy, participants were more concerned about not having to return to repeat a procedure or test. One woman indicated, “I want the doctor to tell me right away without giving me the runaround, if I have an infection, if I have cancer. Perceived Benefits of Self-Sampling for hrHPV Infection The benefits of self-sampling compared with the Pap test were ease, convenience, practicability, less embarrassment, and the lack of need for child care. One participant said, “I guess that is very convenient and more private, less invasive to your personal…you know… . Another woman said, “I would prefer to do it at home. One participant mentioned, “It looks very easy to do, whereas another woman said, “Also because you do it in the comfort of your home, especially if you have kids, you don”t have to ask someone to take care of them while you are gone. Cost was mentioned as a factor in deciding test preference. One participant indicated, “Well, I would pick the cheapest because a lot of times we don”t have medical insurance, and also many times people don”t get checkups due to the lack of money. Another woman said, “I would pick one where I can find out everything without having to do more so it wouldn”t have to be so painful. Perceived Barriers to Self-Sampling for hrHPV Infection One frequently mentioned concern was the fear of not conducting the test correctly. Some participants believed that they would choose a provider to do the testing to ensure that it was done correctly, regardless of any information given to them about self-testing. One woman said, “Oh my God, I think this looks very practical, but I also have the same mentality. I believe there”s nothing better than having a professional do it. Of course you can, how can I say it? I think that if a professional gives us the instructions on how to do it, just how they teach you to use the needles for diabetes; I think we can do it correctly. Another participant said, “I think it could save us the embarrassment, but I would also be doubtful if I did it right or wrong. Other participants, however, believed that if they were taught to do this by a professional or had some sort of indicator that the sample had been collected correctly, they would be able to do the testing themselves. One woman mentioned, “Is there a right or wrong way to do it, … maybe something that can that tell us you did it right. (Moderator: an indicator?) An indicator or something that assures. Another participant said, “Don”t think I would like it, I think the Pap smear is way better. It”s better to go to the doctor because you never know; you might hurt yourself…that”s my personal opinion. Another woman mentioned, “I would prefer this one, if they were to find something abnormal then I would get a more in-depth study. Women in the majority of the groups had concerns about the accuracy of the test:“If this new test is as effective as the other one [Pap test]? and expressed a need for more information about it, including logistics and cost. “Can you buy it in a pharmacy, or do you have to go to a lab? “Would this have the same cost as a Pap smear, or is this less expensive? “I would like to know what the risks are, for example, if this brush gets contaminated with some type of bacteria and if it gets contaminated, then maybe the result would be negative. Discussion In this study, we sought to explore attitudes toward self-sampling for hrHPV infection as a potential method for cervical cancer screening predominantly among Hispanic women who are patients in primary care clinics. This is the first qualitative study on this topic in this population. In all of the groups, most of the participants were aware of cervical cancer, although there were some misconceptions regarding cervical cancer etiology and risk factors. There was a general awareness of the availability of the Pap test as a screening test, and these findings were similar to other studies in Hispanic women.13 We found barriers to regular screening to be consistent with what has been documented in the literature among Hispanic women,27–31 and in this population that lives along the US border with Mexico.13,29,32 Although all of the participants were clinic attendees and had some access to care, they mentioned being aware that lack of a usual source of care and lack of health insurance were the main system-related barriers for many women. Consistent with the literature, women also mentioned other barriers, such as lack of culturally sensitive healthcare services, concerns about pain and discomfort regarding the test, embarrassment, lack of time, lack of awareness, and denial.13,33–36 Unlike other studies regarding Hispanic women,13 language and lack of partner support for this test were not mentioned as barriers. The lack of language as a barrier in this population may be the result of the border location of our setting and the availability of bilingual staff and providers. Although only brief information about self-sampling including accuracy and how to perform it was provided to the women in the focus groups, we found they held a positive attitude toward self-sampling. The acceptability of self-sampling was attributed to perceived benefits such as ease, convenience, less pain, and less embarrassment when compared with the Pap test and how barriers to the Pap test could be overcome with self-sampling. These perceived benefits also have been identified by women in different populations6,37–41; however, we found that cost savings were a potential facilitator for the use of self-sampling, a finding that was not previously reported. Women in all of the focus groups mentioned that they would choose the most inexpensive test (self-sampling vs Pap test) regardless of the other benefits or barriers of each test. The literature supports the existence of high costs associated with the performance of unnecessary cytology for women who do undergo/receive regular screenings.42 Indeed, it has been indicated that half of cervical cytology examinations are unnecessary.42,43 The primary concerns expressed about the self-sampling test were accuracy of the test and low self-efficacy for collecting the sample properly, which has been previously reported.38,44,45 Women expressed the need for education regarding sample collection and reassurance that the sample has been collected properly. This concern was an important factor for some participants in the choice between a Pap test and self-sampling (if this becomes available) for regular screening; therefore, we believe strongly that educating women about a new test, if it were to become available, should include discussions about the test”s accuracy and clear instructions regarding proper sample collection. These discussions will be key to increasing women”s self-efficacy in self-sampling. Our findings have implications for the development of educational materials that should be culturally sensitive and literacy concordant, because several participants mentioned the importance of using words that were easily understandable. These materials also should include information about the differences between self-sampling and the Pap test, that self-sampling is as sensitive as the Pap test in detecting cancer but less specific,7 and that self-sampling can be as sensitive as clinician-collected samples in detecting hrHPV.5 Other areas to address are concerns about contamination affecting results and that the cervix itself may not be sampled. Other logistical questions the participants asked about who and how often to screen, follow-up of the results, setting (over-the-counter vs doctor”s office), and cost cannot be answered because self-sampling for hrHPV infection has not been approved for cervical cancer screening. One of the strengths of our study was that we included women between 30 and 65 years old who fall within the guidelines for cotesting for hrHPV infection. Theoretically, women in this age group are likely beneficiaries of self-sampling if it becomes available. The main limitation of our study was that the focus groups were conducted with primary care patients, who may have different barriers to regular cervical cancer screening than those who do not have access to care; however, most of the women self-reported being underinsured. Another limitation was that we did not inform participants about the possible management guidelines of abnormal results (positive hrHPV test), which could have an impact on participants” preference about testing. We plan to conduct further studies with non–healthcare-seeking women, because they are the ones who may benefit most from self-sampling. Conclusions We found that our population demonstrated positive attitudes toward self-sampling. To increase cervical cancer screening rates in communities with low screening rates, a multiapproach intervention, including an alternative to the Pap test for screening, likely will be highly acceptable. Further research is needed to evaluate the effectiveness of self-sampling in increasing cervical cancer screening rates among nonregular participants in screening programs.
In June 1964, the General Assembly of the World Medical Association (WMA) approved a set of ethical principles for medical research involving human subjects. Named after the city in which it was first adopted, the Declaration of Helsinki quickly gained international significance and has since become one of the flagship documents of the WMA. This year marks the 50th anniversary of the adoption of the Declaration of Helsinki and the importance of this document is more apparent than ever before. Physicians conducting medical research face a paradox: the essential need to ensure the efficacy and safety of interventions by testing them on human subjects, with all the attendant risks, must be reconciled with their fundamental obligation to “do no harm.1 This dilemma was recognized long before the WMA commenced drafting, notably in the 1947 Nuremberg Code, a response to the atrocities committed in the name of medical science by doctors in Nazi Germany.2 The Declaration of Helsinki which was drafted by physicians to provide binding ethical standards for members of their own profession, was the first truly international regulation to address this problem using a pragmatic approach that simultaneously offered real protection. Considerable change has occurred in the last 5 decades in the methods and scope of medical research, which has presented new ethical challenges. These challenges have been addressed in successive revisions of the Declaration as part of the WMA”s regular policy review, most recently in 2013. Although some have argued that the frequency of revisions has undermined its authority,3 the WMA always has considered the Declaration to be a “living document,4 and it is the very fluid nature of the principles it contains that enables it to remain relevant and applicable 50 years on. Despite the emergence of numerous other regulations for medical research involving human subjects, the Declaration of Helsinki remains at the forefront of the provision of ethical guidance. Its influence is derived not from international law, although it does exert considerable authority upon national and international legislation and in some cases it has also been codified into law, but first and foremost upon the fact that it is morally binding for physicians worldwide.5 This primary focus upon the ethical obligations of physicians has been criticized in recent years for leading to internal contradictions in the document and not reflecting the reality of the research environment.6 It does, however, reflect the legal mandate of the WMA as a professional organization of physicians and does not preclude its use by members of other professions. Indeed, a key feature that sets the Declaration of Helsinki apart from other guidelines is its accessibility. Rather than being a detailed rule book, it provides researchers with a concise set of easy-to-read ethical principles. It was of major importance to the workgroup responsible for overseeing the latest revision process that this usability aspect be retained and enhanced. This led to a restructuring of the document, with paragraphs addressing the same topics being reordered under logical subheadings. Adjustments to the language also improved the consistency of the text. The current, eighth version of the Declaration of Helsinki was adopted in Fortaleza, Brazil, in October 2013.7 It represented the culmination of a comprehensive and systematic process of revision, which included international expert conferences on four continents, the final conference taking place in Washington, DC, and an open public consultation during which comments were solicited from the international community.8 Respondents to the public consultation hailed from a vast array of geographical and professional backgrounds and their input highlighted areas of particular controversy. The changes ultimately included in the revised document addressed many of the concerns raised during the revision process and succeeded in balancing the need to promote good-quality clinical research while protecting the rights and safety of research subjects. Protection for vulnerable populations was enhanced, not by including a list of groups or individuals considered particularly vulnerable, which would risk being incomplete, but by providing a general definition (paragraph 19) and setting out a stringent set of conditions for research with vulnerable groups and individuals, including that the group should stand to benefit from the knowledge, practices, or interventions that result from the research (paragraph 20). Criticism that the paragraph on posttrial provisions in the 2008 version was too imprecise9 was addressed by naming those responsible for these provisions and clearly stating that participants are fundamentally entitled to access interventions identified as beneficial in the trial (paragraph 34). Taking into consideration the character of the Declaration, it was not deemed appropriate to go into further detail regarding the form these provisions may take. The rules on ethics committees also were tightened by stating that these must be transparent and their members duly qualified (paragraph 23). Of particular significance was the addition of a paragraph stipulating that compensation must be provided to subjects who are harmed as a result of participating in a study (paragraph 15), and a new requirement that all research studies, rather than merely clinical studies, must be registered (paragraph 35). The latter helps to avoid unnecessary studies and therefore avoidable risks to study participants. A new requirement to disseminate as well as publish research results (paragraph 36) took into consideration concerns expressed by poorer nations that scientific publications are not always internationally accessible. The principles already requiring physicians to seek consent for the collection, storage, and/or reuse of identifiable human material or data were extended to cover biobanks for the first time, and consent must now be informed (paragraph 32). In addition, exceptions to obtaining informed consent are no longer permitted based on a “threat to the validity of the research. One of the main issues of controversy carried over from the previous revision was the question as to what restrictions and conditions should be placed on the use of placebo controls in clinical trials.10 This had been permitted in certain narrowly defined parameters since the 2008 version of the Declaration. The 2013 revision retains the principle that placebo may be used as a comparator when no proven intervention exists or when a proven intervention does exist, only if there are compelling and scientifically sound methodological reasons and if subjects would not be subject to any risk of serious or irreversible harm. This, however, is now addressed more systematically with the regulation also applying to the use of any intervention less effective than the best proven intervention (paragraph 33). Although the recent changes will have few implications for researchers in countries where national regulations already provide a high level of protection for research subjects, the function of the Declaration of Helsinki as an ethical guidance tool, and in particular the new provisions regarding compensation and vulnerable groups, is especially relevant in areas of the world that do not have a sufficiently comprehensive framework of regulations and controls in place.11 This function as an international standard is becoming increasingly important in light of the rapidly progressing globalization of biomedical research and the rise of clinical research outsourcing companies in places such as India.12 That said, and as became clear during the latest revision process, the Declaration is not without its controversial aspects, and conflicts will inevitably persist between those who find it too restrictive and those who see it as too liberal. These reflect fundamentally different ethical positions, which would be impossible to reconcile in any single guideline; therefore, rather than undermining the Declaration, such debates can only strengthen it by promoting a detailed and broad analysis of the ethical considerations, hence keeping the document “alive. In fact, it was precisely the complexity and breadth of these discussions during the latest revision process that demonstrated the exceptional international significance which the Declaration has attained throughout the world during the past half-century. This milestone will be celebrated this year at a WMA meeting attended by the international scientific community in Helsinki, the city of its birth.