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W1981308733 abstract "In 1962, the public passion for averting teratogenicity similar to that resulting from thalidomide led to unanimous passage of the celebrated Kefauver–Harris amendments in the United States (USA) Congress, which allowed the Food and Drug Administration (FDA) to demand more evidence of efficacy and safety from the pharmaceutical industry1. These amendments ultimately provided the Agency with the principles of reproducibility and generalizability as tenets for assertion of efficacy and established the need for safety assessment related to pregnancy. Safety remains the most important aspiration for therapeutics in obstetrics, with new lessons being learned as the physiology of pregnancy becomes better appreciated. The most recent case study of concern involves the FDA-approved medication, 17-hydroxyprogesterone caproate (17-OHPC), and the approach to this class of medication, the progestogens. 17-OHPC is a synthetic progestogen known to have important structural, pharmacokinetic and pharmacodynamic differences from progesterone, the hormone primarily responsible for human reproduction. The most important differences between these drugs are a poorer binding affinity to progesterone receptors by the synthetic (only 26–30% of that of the full agonist progesterone) and the fact that the synthetic drug is not metabolized into a natural progestogen2, 3. Interestingly, the impaired receptor binding is partly a result of the length of the side-chain caproate moiety: the relatively long 6-carbon ester exhibits less receptor affinity than does 17-OHP acetate3. Unfortunately, 17-OHPC is frequently mislabeled as either the natural compound, 17-hydroxyprogesterone (17P), or even progesterone4. This mischaracterization of the synthetic drug as a natural product has potentially contributed to a lack of concern for safety. However, complacency is not justified, as illustrated by another unfortunate case study in obstetrics involving a different synthetic hormone, the estrogen diethylstilbestrol (DES), which caused rare vaginal adenocarcinomas, infertility and pregnancy loss decades after in-utero exposure5. Since the positive study by Meis et al.6, numerous other Phase III trials have tested the same logical paradigm: administer a progesterone receptor agonist in a population of pregnant women with increased susceptibility to preterm birth and hope that an unidentified pharmacodynamic response to enhance progestational physiology is sufficient to alter the primary outcome. The hypothesis presumes that additional progesterone receptor agonism has the potential to influence the functioning of one tissue or a combination of tissues in the reproductive tract to enhance progestational physiology beyond that achievable by exposure to the natural hormone from placental production alone. The possibility that progestational physiological responses are incremental instead of being an all-or-none phenomenon appears biologically plausible given the need for differing responsiveness of the tissues of the reproductive tract to the marked alteration in demand created by advancing gestation itself and by apparent differences between singleton and multiple gestations. The production of progesterone varies by orders of magnitude throughout pregnancy and fold differences are also noted between singleton and multiple pregnancies, all presumably to enhance progestational physiology7. In differing populations clinical trial results have documented alterations, some positive and some negative, in several essential physiological responses. Most notably, cervical performance is improved by progestogen administration, as evidenced by a reduction in the rate of cervical change during the second and early third trimesters reported by several studies, although this observation has not been documented in multiple gestations8-11. Decidual functioning may also be enhanced by supplemental progestogen exposure; one investigation in multiple pregnancies documented a significant increase in birth weight with exposure to natural progesterone in a subset of patients and two studies have demonstrated differences in Cesarean delivery rates12, 13. However, these endpoints allow inference only for altered decidual functioning and further studies are needed. Importantly, several negative pharmacodynamic responses have been observed with exposure to 17-OHPC, including an increase in contraction frequency and lower birth weight14-16. Negative biochemical changes in an inflammatory marker, C-reactive protein, and an endocrine alteration, corticotrophin-releasing hormone concentration, were also identified by Caritis et al.17 in a secondary analysis from a trial in multiple pregnancies. These pharmacodynamic responses reflect potential mechanisms of action for benefit or harm of progestogens. Since natural progesterone has numerous actions via different receptors to promote pregnancy, the issue is not whether progestogens can improve pregnancy outcome, but rather which mechanisms are modifiable and can be enhanced sufficiently in particular populations to achieve identifiable benefit. Strictly speaking, progestogens as a class will have no more potential mechanisms of action to enhance pregnancy outcome than those already possible through the actions of the full progesterone receptor agonist, natural progesterone. Any compound which is not as effective as natural progesterone in promoting progestational physiology mediated by a genomic or a possible non-genomic pathway has the potential to have a negative pharmacodynamic effect. The FDA reviewed the new drug application for 17-OHPC featuring data from a single, positive trial by Meis et al. which was published in 20036. This trial assessed prophylactic administration of the synthetic progestogen in pregnant women with a history of spontaneous preterm birth. Provisional approval was granted in 2011 under subpart H of the Code of Federal Regulations addressing FDA regulatory pathways, but the sponsor was required to demonstrate intent to complete a confirmatory trial. This confirmatory study was designed to be the largest investigation involving either a natural or a synthetic progestogen for the prevention of preterm birth18. Remarkably, this confirmatory trial avoids measurement of cervical length at randomization. Unfortunately, the mechanism by which this synthetic drug alters tissue functions in the reproductive tract at the prescribed dose in order to achieve benefit in this population will therefore likely remain more poorly defined. The confirmatory trial was additionally intended to provide insight into a safety concern for miscarriage identified by the Agency; the FDA review of 17-OHPC highlighted a non-significant difference in pregnancy loss: five in the treatment group vs none in patients administered a placebo (P = 0.175)19. This confirmatory trial continues recruitment. Whatever the outcome, positive or negative, this prophylactic strategy exposes more pregnant women than necessary to intervention, because the indication for treatment is based solely on a history of spontaneous preterm birth rather than evidence of early ongoing pathophysiology or increased risk associated with cervical shortening. As safety is such an important issue in obstetrics, and given the difficulties in proving long-term safety, a prophylactic strategy is not optimal unless the safest of possible interventions is employed. Most recent Phase III investigations evaluating the strategy outlined in the progestogen hypothesis have studied the at-risk population of women with a multiple gestation which is not an inherently pathological state. This is also a situation in which further progestational physiological responses to supplemental progestogen administration are likely diminished due to the increased native placental production already present. Efficacy for prevention of preterm birth with prophylactic administration of progestogens in this population has not been demonstrated. By contrast, and most regrettably, every Phase III study enrolling women with a multiple pregnancy and testing synthetic 17-OHPC has identified a significant increase in adverse events or harm after exposure in either the treatment group or an important subpopulation20. An earlier gestational age at delivery or increased pregnancy loss following exposure to 17-OHPC in multiple gestations has been documented repeatedly and an earlier gestational age at delivery has been correlated with the serum drug concentration15, 17, 21. Remarkably, a recent randomized trial in twin pregnancies with a shortened cervix by Senat et al.22 identified a highly significant increase in earlier preterm birth, < 32 weeks gestation, in evaluated cases with exposure to a higher dose of 17-OHPC, 24/82 (29%) versus 6/79 (8%), P = 0.000522. Preterm birth < 34 weeks was also significantly increased in this group. Tragically, this earlier gestational age at delivery was significantly associated with an increase in perinatal mortality and a composite adverse outcome of stillbirth plus neonatal respiratory distress syndrome23. Other studies have noted a significant increase in neonatal mortality and morbidity with exposure to 17-OHPC21, 24. A significant increase in severe respiratory distress syndrome was observed in the largest trial to date by Lim et al.24, (RR 1.55 (95% CI, 1.01–2.37)), leading to calls for further investigation of progestogen safety24. Finally, a meta-analysis published in this Journal by Sotiriadis et al.25, which included an assessment of 17-OHPC exposure in multiple gestations, quantified a significant increase in a composite adverse outcome which included mortality (RR, 1.211 (95% CI, 1.029–1.425)), with a number needed to harm of 31 (95% CI, 17–167). In the current issue, Mulder et al.26 address another safety concern, the potential for altered fetal growth related to 17-OHPC treatment. This exploratory analysis evaluated fetal biometry data in a subgroup of 104 exposed neonates (52 participants) from the trial by Lim et al.24. The investigation is important as previous randomized, double-blind, placebo-controlled trials in multiples by Combs et al.15 and Caritis et al.16 documented significant increases in the frequency of birth weight < 2500 g and < 1500 g, respectively, in neonates exposed to this synthetic drug15, 16, 20. Mulder et al.26 did not find 17-OHPC adversely influenced fetal growth; however, the number of fetuses and pregnant subjects assessed is insufficient to identify rare growth abnormalities or the potential for developmental toxicity in a susceptible subpopulation. These results do suggest the significant differences in fetal birth weight identified in other studies more likely reflects the gestational age at delivery rather than a growth disturbance associated with exposure. Because 17-OHPC administration in trials enrolling multiples has been repeatedly significantly associated with earlier delivery and harm resulting from complications of prematurity, this synthetic progestogen should not be prescribed or further tested in multiple gestations. Additional evaluations of safety are also indicated. Presumably, harm attributable to the synthetic progestogen is more readily identified in pregnant women with multiple gestations due to the greater susceptibility for interference with the increased physiological demands exerted on the reproductive tract. How this synthetic drug interferes with progestational physiology to limit the duration of pregnancy remains to be defined precisely, but competitive inhibition of progesterone receptor interaction with the natural hormone is suspected. This possibility is supported by a well-planned pharmacodynamic investigation by Caritis et al.17, in which it was observed that an increasing serum concentration of 17-OHPC was significantly positively correlated with serum progesterone concentration, P<0.0001; however, gestational age at delivery was significantly negatively correlated with serum 17-OHPC concentration, P<0.001. Therefore, although increasing serum synthetic progestogen increased bioavailability of the natural hormone, presumably by limiting its hepatic degradation, the increased natural hormone serum concentration could not promote or even maintain progestational physiology in this cohort. Furthermore, in an exploratory secondary analysis derived from the Meis et al.6 trial, Manuck et al.27 noted that particular progesterone receptor polymorphisms were associated with either significant pregnancy prolongation or a significant increase in preterm birth with treatment, verifying that alteration of this receptor's function is a primary target of therapy27. Additionally, Manuck et al.'s findings suggest the safety profile of the FDA-approved synthetic progestogen has not been defined adequately for any population, given a potential pharmacogenomic relationship for treatment response28. This synthetic drug is known to cross the placenta29. Neonatal and long-term outcomes after prolonged fetal exposure to 17-OHPC have not been stratified by maternal or infant progesterone receptor genotype. Also concerning are the physiological effects outside the reproductive tract. Because neurodevelopment appears to be modulated by progesterone receptor agonism and antagonism, potential genetically susceptible subpopulations have not yet been studied sufficiently to exclude untoward events30-32. Given concerns for outcome and development, a cautious approach by regulators and obstetricians to any agent exhibiting antagonism for progesterone receptor function in particular populations appears prudent and further research is needed. In contrast, adverse events or harm have not been found to be significantly increased in Phase III trials testing natural progesterone, in either multiple or singleton asymptomatic pregnancies33. The dosing of natural progesterone utilized in these trials does not result in supraphysiological exposure compared with placental progesterone production at term, especially at term in multiple gestations34. Therefore, preterm administration of the unapproved natural hormone in doses utilized in clinical trials is safer than that of the approved synthetic progestogen. Finally, although safety evaluations are reassuring to date, the safety profile of supplemental natural progesterone requires further study, particularly in other patient populations. These findings raise numerous questions which lead to reconsideration of the original inspirations for the Kefauver–Harris amendments. 1) Is this synthetic drug dangerous for select pregnancy outcomes? 2) Does sufficient evidence exist to demonstrate that 17-OHPC is efficacious to justify more widespread exposure in pregnancy? 3) Most importantly, if pregnant women are treated with an intervention, which select group should be exposed to the safest medication? Diagnostic evaluations including genomics, proteomics, metabolomics and various imaging techniques in concert will inevitably better define the various pathophysiologies which alter normal progestational physiology. Such testing will eventually allow better, targeted treatments and improved methodologies for assessing treatment response. Ultrasound has and undoubtedly will continue to lead the way in the application of objective assessments to define indication for therapy. One of the first Phase III studies utilizing inclusion criteria reflecting a potential pathophysiology was published in 2007 by Fonseca et al.35. These investigators studied a population with marked premature cervical shortening, the test that has repeatedly demonstrated the greatest sensitivity for identifying women and newborns who will potentially suffer morbidity or mortality related to an early preterm birth36, 37. The efficacy findings related to natural progesterone administration in Phase III studies in pregnancies complicated by cervical shortening are noteworthy35, 38, 39. Three such investigations provide more best-evidence for intravaginal natural progesterone to significantly reduce the frequency of early preterm birth than any other therapeutic strategy in the sparse history of obstetric intervention. An individual patient data meta-analysis by Romero et al.33 suggested that a 42% reduction in preterm births < 33 weeks in treated women with a short cervix is possible without identified harm. The recent decision by the FDA should not dissuade practitioners regarding the evidence that has been accumulated; basing therapeutics on objective data that is more likely indicative of early pathophysiology is the optimal way forward for the practice of obstetrics. The conclusion that intravaginal progesterone is efficacious in women with premature cervical shortening was supported by the Society of Maternal Fetal Medicine and the American College of Obstetrics and Gynecology in 201240, 41. Further commentary by ISUOG would be valuable. An appeal by Watson Pharmaceuticals for FDA approval of the natural hormone indicated for premature cervical shortening has been denied, as announced on 26 October 2012, 50 years and 16 days after the Kefauver–Harris amendments were signed into law. To question the decision processes exhibited by the FDA, a large, well-designed comparative analysis between the two distinct progestogens prescribed to prevent preterm birth (intravaginal natural progesterone and intramuscular synthetic 17-OHPC) was recently published by Maher et al.42. A potential justification for lack of approval of the natural hormone could be superior efficacy of the synthetic as a progesterone receptor agonist in the at-risk population in which the Agency has deemed 17-OHPC use to be effective. These investigators found, however, that natural progesterone was superior to the synthetic in preventing preterm birth in women with a history of mid-trimester preterm birth. The rate of preterm birth < 34 weeks was 16.6% in the 253 progesterone-treated participants versus 25.7% in 249 subjects treated with 17-OHPC (RR, 0.58 (95% CI, 0.37–0.89)). A significant difference between the Kaplan–Meier curves for the groups was also identified (P = 0.0023, log rank test)42. These findings support the fundamental concept that natural progesterone is the optimal progestogen to interact with progesterone receptors and potentially prevent preterm birth. In addition, this study found the side-effect profile to be lower with intravaginal treatment compared with intramuscular therapy. This route of therapy also has theoretical safety benefits compared with systemic injections. Similar well-designed studies in higher risk cohorts are needed to validate this observation. Despite the relative wealth of data for this intervention, intravaginal natural progesterone was not approved for premature cervical shortening by the FDA in early 2012. The Agency cited only one sponsored study demonstrating a significant reduction in early preterm birth, with a P-value of 0.02 instead of the desired 0.01 level. However, the original sponsor for this new drug application financially supported two studies, the positive PREGNANT trial, and the earlier progesterone vaginal gel trial which randomized patients based on either obstetric history or cervical length38, 43. In the first trial, the sample size of the co-primary shorter cervix arm was powered to enhance assessment of the therapeutic response along the entire cervical length continuum. Despite decreased enrollment, DeFranco et al.39 still demonstrated that if, at initiation, therapy was directed towards an objective finding, cervical length assessment, a significant difference in preterm birth rates and admission to neonatal intensive care unit could be identified with this treatment. These results were not considered of value by the FDA, even though the definition of cervical shortening was and still has not been defined adequately in a population consisting primarily of women with a history of preterm birth. The optimal cervical length cut-off to provide an indication for treatment for preterm birth prevention will vary based upon the intervention and the patient population. Ultimately, treatment indication and treatment response will not be defined solely by a frequency of cervical length (e.g. < 10th or < 25th percentiles) in any population, but rather by a more thorough assessment of pathophysiology and effectiveness. Although more detailed studies describing treatment indication for intravaginal progesterone as a function of the continuum of cervical length are needed, such evidence should not have been dismissed. In their assessment, the Agency also placed remarkable weight on the country of origin of trial participants44. Sadly, the PREGNANT study further proved that Americans can act more irresponsibly towards preventing adverse outcome than do individuals from other nations, as reflected in poorer compliance rates. Also, the demographics of the PREGNANT study population in the USA did not reflect the entire USA population, raising questions regarding the generalizability premise of the Agency that outcomes observed in American study subjects apply to all Americans. Because premature cervical shortening results from different processes and these etiologies likely vary in frequency in subpopulations exhibiting different risk factors, the findings from the entire PREGNANT study population better reflect the potential for progesterone to alter one or more of these pathophysiologies. However, most assuredly, as highlighted by the FDA, not all women will respond to this intervention, particularly if they do not self-administer the medication. Further research describing factors involved in treatment response are needed, but such study would best be accomplished as Phase IV investigations. The FDA apparently believes that outcomes for American pregnant women will only be enhanced by additional Phase III trials testing intravaginal progesterone primarily in American women and therefore presumably does not believe there is an ethical issue involved in such investigation. Whether placebo-controlled trials could be performed in pregnant women with marked premature cervical shortening is a legitimate ethical question, given the potential morbidity and mortality related to early preterm birth. Would patients, providers, and institutional review boards (IRBs) in the USA and elsewhere allow randomization to placebo if they were aware of reproducible trial results, the recommendations of professional organizations and the safety profile of the intervention? Would IRBs allow randomization to no intervention, given study results testing other interventions such as cerclage or cervical pessary in particular populations? The potential impact of the latest decisions by the FDA regarding this relatively safe, relatively effective, best-in-class progestogen, natural progesterone, is far-reaching for obstetrics, more so than the FDA appreciates. The practice of obstetrics has few approved therapeutics, so problems attributable to any single intervention are magnified. If this therapeutic strategy is to remain viable, safety issues must be addressed promptly and comprehensively. The field's most recent FDA-approved medication for preterm birth prevention, 17-OHPC, has mounting evidence for harm in select populations. A safety issue could have been predicted by the Agency, given that the drug is likely a synthetic partial agonist for progesterone receptors and given that the Agency had itself identified a safety concern. Furthermore, given the history of a pricing debacle related to the synthetic45, many practitioners in the USA often utilize 17-OHPC provided by compounding pharmacies which have their own safety concerns, as was so well documented recently after a meningitis outbreak related to tainted steroids. Therefore, the discipline of obstetrics now faces even greater hurdles for translating the most positive study findings in its history to prevent preterm birth, moving practice towards better objective evidence (cervical length) to justify treatment, providing more cost-effective care and diminishing the use of compounded drugs, in order to further improve outcome and promote the safest practice. The public, politicians, regulators and obstetric providers should be moved by the worsening prematurity observed after exposure to the synthetic drug, especially since a significant increase in previable delivery/death/severe morbidity has been repeatedly observed in individual studies and meta-analysis20-25. Unlike the thalidomide disaster, new legislation to redress wrongs related to the assessment of efficacy and safety of both natural progesterone and synthetic 17-OHPC are unnecessary, as the Kefauver–Harris amendments have long served the USA and other countries well. However, the FDA and other agencies should seriously reconsider the body of evidence, especially safety profiles, when addressing public needs in obstetrics, such as combating preterm birth, and should place greater emphasis on safety. The pressing question is, should a drug's approval in a class of medication be based primarily on improved patient safety, especially if a probable site of action for efficacy is evident from multiple Phase III trials? The desire to protect the smallest and most vulnerable amongst us should again fire some of the same passion directed towards optimizing newborn outcomes as that exhibited 50 years ago. Optimizing risk/benefit and enhancing medication safety are principles our specialty must continually address. Hopefully, any renewed passion will focus on a call for use of the safest medications in obstetrics, especially if a prophylactic strategy is employed, and ultimately to base intervention in pregnant women preferably on a more probable early pathophysiology that is modifiable, in order to minimize unnecessary exposure. Such a direction will move obstetrics, despite the recent antithetical actions of the FDA, closer towards what these amendments were originally intended to accomplish and away from relying on hoped-for pharmacodynamics in more ambiguously defined populations based solely on historical events to possibly improve present outcomes by a more harmful intervention. J. M. O'Brien was involved in studies of progesterone gel treatment for preterm birth prevention sponsored by a maker of progesterone gel; he serves on Advisory Boards and as Consultant for Watson Pharmaceuticals, a company with a financial interest in marketing vaginal progesterone gel for preterm birth prevention; he and others are listed in a patent on the use of progesterone compounds to prevent preterm birth (USA Patent Number 7884093: Progesterone for the Treatment and Prevention of Spontaneous Preterm Birth). J. M. O'Brien has not received any funds from a royalty agreement or licensing of the patent to date nor has his university. He has received funds from Watson within the last year for honorarium at the MHPA Best Practices Award day in Washington, DC (www.mhpa.org/_upload/OBrien-Medicaid-BestPractices-2012-revised.pdf). He was involved in studies38, 43 as a principal investigator published in 2011 and 2007." @default.
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W1981308733 date "2013-08-05" @default.
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W1981308733 title "Medication safety is still an issue in obstetrics 50 years after the Kefauver-Harris amendments: the case of progestogens" @default.
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