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A National Survey Examining Obstetrician Perspectives on Use of 17-Alpha Hydroxyprogesterone Caproate Post-US FDA Approval

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A National Survey Examining Obstetrician Perspectives on Use of 17-Alpha Hydroxyprogesterone Caproate Post-US FDA Approval
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  ORIGINAL RESEARCH ARTICLE A National Survey Examining Obstetrician Perspectiveson Use of 17-Alpha Hydroxyprogesterone CaproatePost-US FDA Approval Andrei Rebarber  • Nathan Fox  • Chad K. Klauser  • Daniel Saltzman  • Ashley S. Roman Published online: 26 June 2013   Springer International Publishing Switzerland 2013 Abstract  Background   A randomized study published in 2003 by theNational Institute of Child Health and Human DevelopmentMaternal Fetal Medicine Units network showed efficacy of 17-alpha hydroxyprogesterone caproate (17P) for the pre-vention of recurrent preterm delivery. Between 2003 and2011 the drug was often provided by compounding phar-macies. In 2011, the US Food and Drug Administration(FDA) approved the drug for this indication. Objective  The objective of this study was to evaluate theimpact of FDA approval on physician attitudes and per-ceptions regarding use of 17P as a drug for preventingrecurrent preterm delivery.  Methods  A 10-min online survey using a structureclosed-ended questionnaire format was designed andadministered from 17 June 2011 to 7 July 2011 among 401obstetricians distributed evenly throughout the USA.  Results  There is nearly universal awareness of 17P for theprevention of preterm birth (93 %), with a large majority(80 %) of obstetricians having reported prescribing themedication. However, surveyed physicians reported thatthe average proportion of eligible patients seen in theirpractice but not prescribed 17P in 2009–2010 was 41 %.Financial and logistical barriers carried the most weight(approximately 75 %) in the decision not to prescribe 17Pto an eligible patient. Forty-one percent of respondentscited lack of FDA approval of 17P as a deterrent to pre-scribing the medication. Thirty-nine percent of respondentshad professional liability concerns regarding prescribingcompounded 17P. Assuming the same out-of-pocketexpense for patients, two-thirds of obstetricians wouldchoose to prescribe Makena  . Conclusion  Awareness of 17P for the prevention of pre-term birth among obstetricians is high. FDA-approvedmedications seem to have physician preference due toenhanced assurance for product efficacy and safety. 1 Introduction Preterm birth is the leading cause of perinatal mortality andmorbidity for non-anomalous infants in the USA, wheremore than 12 % of infants, approximately 480,000, areborn prematurely each year [2]. Though past studies of progestational agents for the prevention of preterm deliveryreported varied results dating back to the early 1970s, therewas renewed interest in the use of 17-alpha hydroxypro-gesterone caproate (17P) as a secondary preterm birthprevention strategy following publication of the study fromthe National Institute of Child Health and Human Devel-opment (NICHD) Maternal–Fetal Medicine Units (MFMU)Network [1, 3]. The NICHD-MFMU Network study examined the effectiveness of 17P in reducing the rate of preterm delivery in women carrying a singleton gestation A. Rebarber    N. Fox    C. K. Klauser    D. Saltzman   A. S. RomanCarnegie Imaging for Women, PLLC, New York, NY, USAA. Rebarber    N. Fox    C. K. Klauser    D. Saltzman   A. S. Roman ( & )Department of Obstetrics and Gynecology,NYU School of Medicine, New York, NY, USAe-mail: aroman@mfmnyc.comA. Rebarber    N. Fox    C. K. Klauser    D. Saltzman   A. S. RomanDepartment of Obstetrics and Gynecology,Mount Sinai School of Medicine, New York, NY, USAA. Rebarber70 East 90th Street, New York, NY 10128, USAe-mail: arebarber@mfmnyc.comClin Drug Investig (2013) 33:571–577DOI 10.1007/s40261-013-0099-4  and with a history of a spontaneous singleton pretermdelivery. 17P was administered via weekly injections ini-tiated between 16 and 20 weeks’ gestation and was shownto decrease the incidence of recurrent preterm birth in thestudy population by 33 % [3]. A meta-analysis includingboth older and current studies has provided further supportfor the use of 17P for preterm birth prevention [4], thoughthe mechanism of action by which 17P prevents pretermbirth remains poorly understood.In February 2011, Makena  (17P; manufactured byBaxter Pharmaceutical Solutions, Bloomington, IN, USA,for Ther-Rx Corporation, St. Louis, MO, USA) wasapproved by the US Food and Drug Administration (FDA)indicated specifically for the reduction of risk of pretermbirth in women who are pregnant with a single baby andhave spontaneously delivered a singleton gestation pre-term. Prior to approval, pregnant women may haveobtained the active ingredient 17P through compoundingpharmacies. On 30 March 2011, in order to support accessto 17P, the US FDA stated that it will not prevent com-pounding pharmacies from continuing to produce validprescriptions for 17P [5]. It is important to note that despitethe availability of compounded 17P following the publi-cation of Meis et al. [1], there may have been barriers todrug access and utilization by the very fact that the med-ication lacked FDA approval.The aims of the present study were to better understandthe attitudes of obstetricians when it comes to prescribingdrugs to patients during pregnancy, measure awareness andestimated proportion of subjects prescribed 17P reported bygeneral obstetricians and better understand their percep-tions of 17P, identify unmet needs associated with com-pounded 17P from the perspective of obstetricians, andfinally to evaluate the impact of FDA approval of Makena  on perceptions of accessibility, safety, and cost amongobstetricians. 2 Methods A 10-min online survey was completed from 17 June to 7July 2011 among 401 obstetricians divided approximatelyequally between the four census-defined regions of theUSA (South, West, Midwest, Northeast). The survey wascommissioned by Ther-Rx Corporation but conducted byan independent company, Kelton Research. The surveyexcluded obstetricians from Massachusetts, WashingtonD.C., Maine, Vermont, and Minnesota due to state regu-latory preclusions to allow participation. In order to qualifyfor the survey the respondents had to indicate obstetrics/ gynecology as their primary medical practice, have been inpractice for at least 3 years (i.e. obtained their certificationin 2008 or earlier) and see a monthly minimum of fivepatients at risk for preterm birth due to prior singletonspontaneous preterm delivery before 37 completed weeksof gestation. Those indicating ‘‘maternal–fetal medicine’’were excluded from participation to focus survey results ongeneral obstetrician-gynecologists. The design called for400 physicians stratified by region leading to a margin of error in this report of 4.9 % at a 95 % confidence interval.To ensure the validity of the results the following stepswere taken: (1) this was a blind survey in that at no pointwas the sponsor of the survey revealed to the respondents;(2) invitations to participate in this survey were sent by athird-party sample partner to 13,882 physicians, including5,942 listing a specialty of obstetrics and gynecology,1,193 listing gynecology, and 6,742 listing obstetrics tolimit sampling bias; (3) after targeting for medical spe-cialty, the first 100 qualified physicians in each region wereincluded; and (4) the invitation to participate in the surveywas objective and did not make reference to 17P, Make-na  , or pregnancy-related prescription drugs, therebyreducing respondents self-selection. For statistical analysis,groups were compared using chi-squared ( v 2 ) or FisherExact test where appropriate, with  p \ 0.05 defined assignificance. Physicians received a nominal fee for partic-ipating in the study. 3 Results Characteristics of the obstetricians surveyed are shown inTable 1. The majority of obstetricians indicated that FDAapproval and regulation is important to them when theyprescribe medications during pregnancy. Of the 401obstetricians, 314 (78 %) indicated that drug approval bythe FDA for safety and efficacy was either ‘very important’or ‘somewhat important’ when deciding to prescribe amedication (Fig. 1). Of the 401 subjects, 336 (84 %)thought it was either ‘very important’ (223 or 56 %) or‘somewhat important’ (113 or 28 %) that a drug is manu-factured using methods that ensure purity of ingredients,potency of product, and dose consistency, while only 46(11 %) felt this was ‘very unimportant’. Finally, 320(80 %) of the 401 obstetricians responded that they dis-agree with the idea that a separate written consent form isnecessary for FDA-approved products.With regard to obstetricians’ awareness of progestationalagents associated with a reduction in risk of recurrent pre-term birth, 373/401 (93 %) of obstetricians surveyed iden-tified compounded 17P and 345 (86 %) identified Makena  (Fig. 2). Awareness of compounded 17P was highest in theNortheast (98/100 [98 %]), which was significantly higherthanintheMidwest(91/100[91 %];  p  =  0.03)andtheWest(88/99[89 %];  p  =  0.01).Additionally,195/401(49 %)and306/401(76 %)ofobstetricianssurveyedindicatedthatthey 572 A. Rebarber et al.  wereawareoftheuseoforalprogesteronetabletsandvaginalgel or suppositories, respectively, to reduce the risk of spontaneous preterm birth. A large majority of the 401obstetriciansclaimtohaveprescribedcompounded17P(319[80 %]) but only 99 (25 %) of them have prescribed theFDA-approved Makena  (Fig. 3). Prescription rates, how-ever, are not equal across the country. Obstetricians in theWest were less likely to prescribe compounded 17P than therest of the country: 71/99 (71 %) versus 248/302 (82 %);  p  =  0.03.Prescriptionof17Pwasalsosignificantlyhigherincities/suburbs than in small towns/rural areas: 243/295(82 %) versus 76/106 (72 %);  p  =  0.02. Only 93 (29 %) of the 319 obstetricians that reported prescribing compounded17Pin2009–2010indicatedthattheyprescribed17Pto90 %of those patients defined as eligible (i.e. prior history of aspontaneous singleton preterm birth).Surveyed physicians reported that the average proportionof eligible patients seen in their practice but not prescribed17Pin2009–2010was41 %(Fig. 4).Out-of-pocketcoststouninsured and low-income insured patients appear to weighmostheavilywithregardstothedecisionnottoprescribe17Ptoaneligiblepatient.Ofthe334obstetricianswhoprescribed17P to less than 100 % of their eligible patients, 258 (77 %)indicated that financial burden was ‘very important’ or‘somewhat important’ in that decision. Additionally,212/334(63 %)obstetriciansindicatedthepatient’sinabilityto find a local pharmacy to compound the drug was ‘veryimportant’ or ‘somewhat important’ in their decision not toprescribe17P.Professionalliabilitydidnotseemtoprovideasignificant barrier to prescribing the drug in eligible patientsas only 41 (12 %) found this to be a ‘very important’ factor(Figs. 5, 6). Approximately 261 (70 %) of the 373 obstetricians whowere aware of 17P indicated that they cannot verify thequality of ingredients in 17P, i.e. its consistency, purity, andpotency, when compounding pharmacies are used for thisproduct. Nearly half (172/373 [46 %]) of these obstetricianseither‘somewhatagreed’or‘completelyagreed’thatthereisgreater professional liability when prescribing compounded17P if an FDA-approved product is available (Fig. 6).Finally, specifically with regard to Makena  , 343 (86 %) of the 401 obstetricians indicated that all patients, regardless of socioeconomic status, should have access to FDA-approvedMakena  . 270 (67 %) of obstetricians expect Makena  tocostmorethancompounded17Pand,moreimportantly,266(66 %) of obstetricians would choose to prescribe Makena  if the same out-of-pocket expense for the drug was incurredby the patient when compared with compounded 17P use.153(38 %)ofobstetriciansdisagreedwiththestatementthat‘‘If I were to objectively inform my patients about the dif-ferences, the vast majority of them would prefer Makena  ’’. 4 Discussion Several important new findings can be gleaned from thisnational survey that may help elucidate obstetrician pre-scribing patterns. In the past, two previous publicationshave attempted to understand physician perspectives on useof progestins for the prevention of preterm birth [6, 7]. In 2005, Ness and coworkers [6, 7] evaluated Maternal Fetal Medicine (MFM) specialist use and attitudes regardingprogesterone for the preventative treatment of pretermbirth. With a 45 % response rate (572/1,264), the authors Table 1  Characteristics of obstetricians surveyedCharacteristic  n  (%) a Sex Male 278 (69)Female 123 (31) Region Northeast 100 (25)Midwest 100 (25)South 102 (25)West 99 (25) Location Small city/town 90 (22)Large city/urban area 109 (27)Suburbs of a large city 186 (46)Rural area 16 (4) Year of certification \ 1980 31 (8)1980–1989 118 (29)1990–1999 109 (42)2000–2007 83 (21) Time spent in patient care (%) 100 178 (44)90–99 185 (46)80–89 22 (5) \ 80 16 (4) Number with prior preterm birth treated/month B 5 65 (16)6–10 129 (32)11–15 38 (9)16–20 57 (14)21–25 27 (7)26–30 24 (6) C 31 61 (15) Patient insurance type [median percentage (range)] Commercial 75 (0–100)Medicaid 20 (0–100)Uninsured 5 (0–80) a Except where otherwise indicatedObstetrician Perspectives on 17P 573  noted 67 % of respondents used progesterone in theirclinical practice with the most frequent indication beingprior spontaneous preterm birth \ 34 weeks (41 %). Theauthors also noted that some of the main reasons that MFMphysicians cited for patients declining therapy includedlack of insurance coverage (62 %) and concerns about risks(42 %). They also noted that ‘‘nonusers were significantlymore concerned about safety, efficacy, lack of FDAapproval, and liability than users’’. Henderson and col-leagues [6, 7] in 2007 had a 52 % response rate to their survey comprising almost 90 % general obstetriciangynecologists. Their results suggested that more than 90 %of progesterone users used the drug for the prevention of preterm birth in patients with a prior history of pretermbirth and the intramuscular administration route wasoverwhelmingly preferred (83 %). Additionally, almostone-third of respondents used the drug for other indica-tions. Finally, more than one-third were very concernedthat it was not easily available (36 %), not covered byinsurance (31 %), or that there may be long-term fetal orneonatal effects (27 %). After two committee opinionsissued by the American College of Obstetricians andGynecologists (ACOG) in 2003 and 2008 [8, 9], there appears to be widespread clinical acceptance for proges-terone treatment for the prevention of preterm birth insingleton gestations among MFMs and general obstetriciangynecologists. However, a significant portion of eligiblepatients throughout the country are not treated due tofinancial and logistic barriers, as well as possible unfoun-ded practitioner/patient concerns regarding fetal/neonataluntoward effects. Our survey further substantiates theseconcerns as while there is a high awareness of 17P for the 020406080100 Drug is manufactured using methods that ensure purity of ingredients, potency of product, and dose consistencyDrug is approved by FDA after review for safety and effectivenessDrug is produced in a facility that complies with the FDA's GMP requirements and has required periodic inspectionsPost-marketing surveillance to document, analyze, and report adverse events to the FDADrug is dispensed with complete and consistent prescribing information reviewed and approved by the FDADrug is dispensed with education materials and standardized FDA-approved patient labelingStandardized distribution of the drug across the country Percentage Very importantSomewhat importantSomewhat unimportantVery unimportant Fig. 1  Obstetrician assessment of importance of drug properties.  FDA  US Food and Drug Administration,  GMP  good manufacturing processes 0102030405060708090100 17P injectionsMakena  ®  Progesterone vaginal gel or suppositoriesOral progesterone tablets    O   b  s   t  e   t  r   i  c   i  a  n  s  a  w  a  r  e  o   f  p  r  o  g  e  s   t  a   t   i  o  n  a   l  a  g  e  n   t  s   t   h  a   t  r  e   d  u  c  e  r  e  c  u  r  r  e  n   t  p  r  e   t  e  r  m    b   i  r   t   h   (   %   ) Fig. 2  Proportion of obstetricians aware of drugs toreduce the risk of preterm birth. 17P  17-alphahydroxyprogesterone caproate574 A. Rebarber et al.  treatment of preterm birth on average, surveyed physiciansreported that the average proportion of eligible patientsseen in their practice but not prescribed 17P in 2009–2010was 41 %. It is possible that some of these subjectsreceived other forms of progesterone. A surprisingly largegroup of obstetricians indicated that vaginal progesteronegel or suppositories may be used to prevent preterm birth,despite mixed data to suggest efficacy for subjects with aprior preterm birth [10, 11]. Our results suggest that the proportion of physiciansaware of 17P varies by region. While this is a statisticallysignificant result, the practical implication of this result isuncertain.US FDA approval of 17P may improve obstetriciandecisions to prescribe 17P as it was identified as a majorbarrier for affecting prescribing patterns as evident inrecent publications [6]. Most obstetricians agree that theycannot verify the quality of ingredients in compounded 17Psuch as its consistency, purity, and potency. Theseconcerns have been validated in another progestationalagent where a comparison was made between compoundedvaginal progesterone suppositories with the FDA-approveddrug Crinone  . This study found that only one of tencompounding pharmacies randomly chosen provided sup-positories that were all within the potency limits for theprescription. The compounded product from one pharmacydemonstrated evidence of microbial contamination inspecimens. Furthermore, the pH of the compoundedproduct was significantly higher than the FDA-approvedgel product. The authors concluded that the quality of compounded drug was inconsistent from pharmacy topharmacy and that reproducible drug delivery cannot beguaranteed with compounded products [12].Nearly half of obstetricians also indicated that there ismore professional liability with prescribing compounded17P if an FDA-approved product is available. Additionally,the majority of obstetricians surveyed indicated that patientpreference for the FDA-approved product would be present 0102030405060708090100 17P injectionsMakena  ®  Progesterone vaginal gelor suppositoriesOral progesterone tablets    O   b  s   t  e   t  r   i  c   i  a  n  s  p  r  e  s  c  r   i   b   i  n  g   d  r  u  g  s   t  o  r  e   d  u  c  e   t   h  e  r   i  s   k  o   f  p  r  e   t  e  r  m    b   i  r   t   h   (   %   ) Fig. 3  Proportion of obstetricians prescribing drugsto reduce the risk of pretermbirth.  17P  17-alphahydroxyprogesterone caproate 01020304050607080901000 - 910 - 1920 - 2930 - 3940 - 4950 - 5960 - 6970 - 7980 - 8990 - 100 Percentage category    E   l   i  g   i   b   l  e  s  u   b   j  e  c   t  s  p  r  e  s  c  r   i   b  e   d   1   7   P   (   %   ) Fig. 4  Obstetrician-reportedproportion of eligible subjectsprescribed 17-alphahydroxyprogesterone caproate(17P). The average percent of eligible subjects prescribed 17Pis 59 %Obstetrician Perspectives on 17P 575
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