Common chemistry, manufacturing, and control deficiencies in abbreviated new drug applications assessed by the US Food and drug administration: Hurdle to access cost-effective medicines.

To market a generic product in the United States, it must be registered in Common Technical Document (CTD) format with the US Food and Drug Administration. The Generic Drug User Fee Act went into force in 2012, to expedite the timely review of Abbreviated New Drug Applications (ANDA) by communicating potential defects in the application to the applicant through deficiency letters at different time intervals during the review cycle. This often delays product approval since these deficiencies must be resolved before the product can be approved. In the present study, a study was performed to analyze the recurrent queries for ANDA applications in the CTD quality module from 2013 to 2020, and the probable corrective and preventive action to be taken was drafted. The most frequently occurring queries were observed in the sections titled "Description of manufacturing process and process controls", "Controls of critical steps and intermediates", "Specifications (Control of drug product)", and "Stability data".

Cellular Agriculture: Opportunities and Challenges.

Cellular agriculture is the controlled and sustainable manufacture of agricultural products with cells and tissues without plant or animal involvement. Today, microorganisms cultivated in bioreactors already produce egg and milk proteins, sweeteners, and flavors for human nutrition as well as leather and fibers for shoes, bags, and textiles. Furthermore, plant cell and tissue cultures provide ingredients that stimulate the immune system and improve skin texture, with another precommercial cellular agriculture product, in vitro meat, currently receiving a great deal of attention. All these approaches could assist traditional agriculture in continuing to provide for the dietary requirements of a growing world population while freeing up important resources such as arable land. Despite early successes, challenges remain and are discussed in this review, with a focus on production processes involving plant and animal cell and tissue cultures.

Innovations in vascular and endovascular surgery in Brazil: a data analysis study / Inovações em cirurgia vascular e endovascular no Brasil: uma análise de dados

Background: Innovations in vascular and endovascular surgery have important social and economic repercussions. Most endovascular devices used in Brazil are imported and, therefore, particularly expensive. Objective: To conduct a retrospective analysis of patent and regulatory approval data for newly developed vascular and endovascular devices, based on the number of patents registered at the Brazilian National Industrial Property Institute (INPI) and the number of products approved by the National Health Surveillance Agency (ANVISA) over recent years. Methods: This retrospective study involved electronic searches of the INPI (www.inpi.gov.br) and ANVISA websites (www.anvisa.gov.br), for patents registered and products approved between January 1997 and December 2012. Results: The keywords used for the search ("catheter(s)," "stent(s)," "graft(s)," and "wound dressing(s)") returned a total of 701 new patents registered during the period studied. Thirty-four percent (n=237) of these were patents for wound dressings, while the remaining 66% (n=464) were for devices used in endovascular surgery. Only 7.8% (n=268) of the 3433 products approved by ANVISA during the period analyzed were produced in Brazil. Conclusions: The social and economic importance of innovations in health care highlights the need to monitor them, to register them and to support their production, in view of the need to develop local alternatives to imported health care technology. .

Contexto: As inovações em cirurgia vascular e endovascular são responsáveis por grande impacto econômico e importância social. Em sua grande maioria, os materiais são importados, onerando ainda mais o seu custo. Objetivo: Realizar uma análise retrospectiva dos Registros de Patentes e da liberação para utilização dos produtos do segmento da cirurgia vascular e endovascular, de acordo com o número de patentes depositadas no Instituto Nacional de Propriedade Industrial (INPI) e as publicações deferidas autorizando utilização dos produtos pela Agência Nacional de Vigilância Sanitária (ANVISA), nos últimos anos. Método: Estudo retrospectivo, no período de janeiro de 1997 a dezembro de 2012, por meio de pesquisa de dados eletrônicos no site do INPI e dados referentes à liberação para utilização de produtos médicos no site da ANVISA. Resultados: Encontraram-se 701 registros de novas patentes referentes a inovações tecnológicas na área de cirurgia vascular e endovascular, com os termos pesquisados 'cateter(es)', 'stent(s)', 'endoprótese(s)']. Destes, 34% (n=237) foram referentes a registros de patentes de novos curativos e 66% (n=464), de materiais utilizáveis em cirurgia endovascular. Dentre os 3.433 novos registros liberados pela ANVISA, aproximadamente 7,8% (n=268) são de produtos fabricados no Brasil. Conclusões: A importância econômica e social das inovações em saúde demonstra o quão importante é a sua monitorização, o seu registro e o apoio para sua produção, com a visão da necessidade do desenvolvimento de soluções nacionais para este mercado. .

Evaluation of the Gulf Cooperation Council Centralized Procedure: The Way Forward.

The aim of the study was to evaluate the Gulf Cooperation Council (GCC) centralized regulatory review process. Regulatory review times-including submission and application dates for new active substances (NASs) and existing active substances (EASs) using a standardized template for the period of 2006 to 2010-were collected directly from the GCC office located in Riyadh, Saudi Arabia. A total of 413 products (96 NASs and 317 EASs) were approved during the period, with an overall significant increase in the EASs ( P < .001). The median approval times increased from 107 calendar days in 2006 to 265 in 2010 ( P < .001). The lowest approval time was for EASs submitted by the Gulf companies (134 days) and the longest for NASs submitted by international companies (346 days) ( P < .001). These data were also analyzed according to therapeutic classes and dosage forms. The results also showed that the lowest number (n = 16) approved during the period was in 2010, and this was due to a major regulatory change implementing the International Conference on Harmonisation product stability guideline for the region. The findings indicate that the delay and the wide range in approval times could be reduced by utilizing a standard assessment template for product review and the implementation of a clock stop system for company responses to questions from the GCC central registration committee. Furthermore, using information technology tools would speed up the registration process rather than the manual exchange of product registration files between the executive office and the member states.

Anti-infective medicine quality: analysis of basic product quality by approval status and country of manufacture.

BACKGROUND: Some medicines for sale in developing countries are approved by a stringent regulatory authority (SRA) or the World Health Organization (WHO) prequalification program; many of these are global brands. This study ascertains whether medicines approved by SRAs or the WHO perform better in simple quality tests than those that have not been approved by either. METHODS: Over the past 4 years, 2652 essential drugs (products to treat malaria, tuberculosis, and bacterial infections) were procured by covert shoppers from eleven African cities and eight cities in a variety of mid-income nations. All samples were assessed using the Global Pharma Health Fund eV Minilab® protocol to identify whether they were substandard, degraded, or counterfeit. RESULTS: The failure rate among SRA-approved products was 1.01%, among WHO-approved products was 6.80%, and 13.01% among products that were not approved by either. African cities had a greater proportion of SRA- or WHO-approved products (31.50%) than Indian cities (26.57%), but they also experienced a higher failure rate (14.21%) than Indian cities (7.83%). The remainder of cities tested had both the highest proportion of approved products at 34.46% and the lowest failure rate at 2.70%. Products made in Africa had the highest failure rate at 25.77%, followed by Chinese products at 15.74%, Indian products at 3.70%, and European/US products, which failed least often, at 1.70%. Most worrying is that 17.65% of Chinese products approved by the WHO failed. CONCLUSION: The results strongly indicate that approval by either an SRA or the WHO is correlated with higher medicine quality at a statistically significant level. The comparatively high failure rates among WHO-approved products suggest there may be some weakness in post-marketing surveillance of these products, especially of Chinese-made WHO-approved products. The discrepancy between the failure rate of WHO-approved products from India (2.39%) and China (17.65%) is cause for concern. It is possible that more of the failures originating in China are counterfeit products, but this cannot be ascertained without greater help from the manufacturers themselves.

In vitro assessment of the structural integrity of the female condom after multiple wash, dry, and re-lubrication cycles.

Since the introduction of the female condom in the early 90s, there have been numerous reports of reuse of the device. In response to these reports, studies were undertaken to evaluate the safety of female condom reuse. If reuse were shown to be safe, then programmatic costs of introduction of the female condom would be reduced allowing it to be more widely available. This article outlines the results of in vitro structural integrity testing of the female condom after multiple wash, dry, and re-lubrication cycles. Devices were tested up to 10 washes using water leakage, burst, and tensile seam testing. All results were compared to the United States Food and Drug Administration (US FDA) standards for an unused female condom. The results of the structural integrity tests for all 6 washing procedures examined in this study were above the FDA minimum standards for seam strength and burst tests. For the water leakage test, 3 of 6 washing procedures tested passed the required FDA minimum standards (no holes detected). From the results of the study, it seems that washing, drying, and re-lubricating the female condom up to 10 times leads to some deterioration in the structural integrity of the device for specified washing procedures. Further studies are currently being conducted to establish the safety of female condom reuse with respect to microbial retention, structural integrity after in vivo use, and viral permeability.

Evaluating vaccine safety before and after licensure.

PIP: This paper discusses an evaluation approach for vaccine safety before and after licensure. The current approach to evaluating new vaccines divides prelicensure evaluations into three phases (Phase 1-3 trials). A new vaccine initially undergoes a Phase 1 trial in a small number of adults, and if it performs well in this phase, it then proceeds to a Phase 2 trial and then to a Phase 3 trial for large-scale testing. When a new vaccine performs well in these three phases, a license is given for its employment with all populations at risk for the disease targeted. There are instances when lapses occur during the prelicensure evaluative sequence. Even though these instances do not invalidate the current paradigm for Phase 1-3 trials as a basis for vaccine licensure, such events inevitably reduce public confidence in the producers, regulators, evaluators, and deliverers of vaccines. In order to prevent such occurrences, postlicensure evaluations of vaccine safety using computerized, large linked population databases are recommended.^ieng

Duramed Pharmaceuticals targets women's health.

PIP: In August 1999, the US Food and Drug Administration (FDA) approved Apri, a new oral contraceptive from Duramed Pharmaceuticals. Apri is available at approximately 30% less than the retail cost of comparable pills and is the first substitutable product equivalent to Ortho-Cept and Desogen, both of which contain 30 mcg of ethinyl estradiol and 150 mcg of desogestrel. Duramed, a longtime manufacturer of generic pharmaceuticals, has gained FDA approval for other women's health products in the last 2 years, including 1) medroxyprogesterone acetate tablets for treatment of secondary amenorrhea and abnormal uterine bleeding due to hormonal imbalance, 2) estropipate tablets for treatment of vasomotor symptoms of menopause and prevention of osteoporosis, and 3) estradiol tablets. In March 1999, Duramed also gained FDA approval for Cenestin, a conjugated estrogen drug product that is made of 9 synthetic estrogen components derived from a compound obtained from plant material. This drug is safe for short-term use in treating vasomotor symptoms such as hot flashes and sweating associated with menopause.^ieng

Mifepristone approval delayed, supporters look to action by FDA.

PIP: Although the US Food and Drug Administration (FDA) has again delayed action on marketing approval of the abortion drug mifepristone, supporters are using the time to continue provider training, education, and research of the medical abortion option. While FDA says it needs more information before reaching a decision on whether the drug will be made available in the US, it issued an approval letter on the mifepristone/misoprostol drug regimen, which echoed its original action of September 18, 1996. An approval letter is an action frequently used by the FDA to indicate that safety and efficacy data have passed agency review but additional information must be submitted before final approval for marketing is given. While the FDA approval process is moving forward, the National Abortion Federation (NAF) has held 12 provider training sessions this year, with presentations scheduled at several national professional provider organizations. NAF is also developing educational materials on mifepristone for patients and providers.^ieng

FemCap in Germany, seeking U.S. approval.

PIP: FemCap is a vaginal barrier device for contraception for which approval is being sought from the US Food and Drug Administration. It is a silicone rubber that resembles the shape of a sailor's hat, with a dome that covers the cervix, a rim that fits into the cornices, and a brim that forms a seal against the vaginal wall and acts as a funnel to direct ejaculate fluid into the groove. This product is already available in Germany, Australia, and Switzerland. It comes in 3 sizes: small (22 mm), for women who have never been pregnant; medium (26 mm), for women who have been pregnant but have not had a vaginal delivery; large (30 mm), for women who have had a vaginal delivery. The advantages of this product include prevention of spread of sexually transmitted diseases, provision of contraception when needed without daily action required, no hormonal side effects, no effect on breast milk, can be stopped anytime, and easy to use. Development research that offers a strap for ease of removal is under way, while an efficacy study that compared the device with the diaphragm indicates that both performed in the range of most barrier methods.^ieng

Mirena intrauterine system seeks U.S. nod.

PIP: Mirena, the levonorgestrel intrauterine system, is seeking approval from the US Food and Drug Administration, with Berlex Laboratories filing a new drug application with the agency. National family planning experts have been calling for US introduction of this unique intrauterine contraceptive that delivers a 20 mcg daily dose of locally acting hormone directly in the uterus since 1990. Several health experts indicated that Mirena would provide American women with the convenience and high contraceptive efficacy characteristics of IUDs while reducing menstrual flow and cramps. However, since Mirena has a different insertion procedure from previous devices, it will require hands-on instruction. In view of this, a proprietary device is developed which should aid in inserting the IUD. Appropriate physician education and patient support programs will accompany the product upon approval.^ieng

German drug agency approves mifepristone.

PIP: This brief article discusses the availability of mifepristone in Germany. The Federal Drug Agency in Berlin announced the approval of the application for sale of mifepristone from its French manufacturer, Laboratoires Exelgyn, Paris. The drug will be available to German women needing abortions during the first seven weeks of pregnancy. Administration of the drug should be followed two days later by the insertion of a prostaglandin pessary. The Social Democrat family minister, Christine Bergmann, has said that she considers the drug an important alternative to surgical abortion. However, it has met with disapproval from the Roman Catholic Church and some conservative politicians. Gynecologists have stressed that the final decision lies entirely with the woman seeking an abortion.^ieng

The pill in Japan: will approval ever come?

PIP: The Japanese Ministry of Health and Welfare voted in March 1998 to indefinitely delay the licensing of oral contraceptives in Japan. Over years of attempts to gain approval of the pill for contraception, health officials have cited a range of reasons for their position against the pill, including concern over side effects, fears about the potential spread of sexually transmitted diseases if pill use replaces condom use, and worries about the environmental effects of hormonal contraceptive use. Japan is unique in banning all hormonal methods of contraception. The author describes the history of hormonal agents in Japan, from their initial approval in the country for noncontraceptive therapeutic uses in the late 1950s through the defeat in March 1998. Given the higher failure rates associated with condom use and fertility awareness, it is no wonder that abortion is rather common in Japan. Making hormonal methods of contraception available would help to prevent unwanted pregnancies. The uphill battle to legalize the low-dose pill in Japan continues.^ieng

Putting evidence into practice.

PIP: Clinical effectiveness is defined as the extent to which specific clinical interventions, when used in the field for a particular patient or population, do what they are intended to do. The evidence base for achieving clinical effectiveness in family planning is improving mainly because fertility control is a high international public health priority. Evidence generated by methodologically sound and substantial international research programs means that family planning services can make major strides toward achieving clinical effectiveness by investing in methods already shown to work effectively and acceptably. The WHO trial of emergency contraceptive (EC) regimens published in the Lancet earlier in the year is an example. A large, well-conducted, randomized controlled trial found the progestogen-only regimen to be more effective and better tolerated than the combined estrogen-progestogen regimen. Trial results also strongly suggest that both regimens are more effective in preventing pregnancy when taken earlier in the 72-hour window after unprotected sex. Some researchers, however, are discouraging the abandonment of the combined regimen in favor of the progestogen-only approach. While it remains to be seen whether the WHO trial results will be duplicated in future research or translate directly to the UK population, it is unlikely that the study's key findings will be reversed by future research. The lack of a licensed progestogen-only EC formulation places the UK's family planning field in an unsatisfactory interim situation.^ieng

Japanese pill approval is bittersweet.

PIP: This article reports the controversy over the approval of a birth control pill in Japan. The birth control pill underwent a 9-year deliberation before it was approved in June as compared with the male impotence drug Viagra, which gained a quick approval from the government. Such quick approval made women's groups feel that this was characteristic of a societal bias. For years, the health ministers delayed the approval because supposedly more research was needed to determine the pill's safety and because of other reasons cited. What bothered these women's groups was the fact that the government kept citing the reason of safety as the cause of the delay, while, on the other hand, Viagra has claimed two lives since its approval. In this sense, many believe that culture still matters in Japan and such actions can be considered a gender issue.^ieng

The political challenges and educational opportunities around very early abortion.

PIP: In 1998, the US House of Representatives amended an appropriations bill to prohibit the US Food and Drug Administration (FDA) from approving abortifacients. While it would have had broader implications, this amendment targeted mifepristone, which has been used since 1988 in France to cause early medical abortions. The measure failed to gain the support of the Senate after opponents argued that it would represent an inappropriate interference of the Congress into scientific processes and pointed out that mifepristone is a promising treatment for other conditions, such as Cushing's syndrome and endometriosis. Mifepristone is just one of a number of emerging technologies that allow women to obtain abortions at very early stages of pregnancy. Most public support for abortion is directed to early abortion, and most US women have early abortions (50% in the first eight weeks, and 90% in the first trimester). A 1997 poll revealed that the US public is largely uninformed about drugs used for early abortion, such as mifepristone or the cancer-fighting drug methotrexate, which is being used off-label as an abortifacient. However, 4200 medical abortions were performed in the US in 1996, and this figure increased to 4300 in the first half of 1997. The public must be informed that the process of medical abortion is not as simple as "popping a pill" but requires several days of medical supervision. In France, the abortion rate has declined since mifepristone was introduced.^ieng

Emergency contraceptives bring a little peace of mind.

PIP: Although emergency contraceptive pills have been prescribed to US women since the discovery of the birth control pill, this regimen has been termed "America's best-kept secret." For fear of legal liability, many providers have been unwilling to prescribe oral contraceptive pills for a purpose other than that for which they are labeled on the packaging. There are indications, however, that access to emergency contraception in the US is improving. PREVEN, the first product to be approved by the US Food and Drug Administration specifically for emergency contraception, was released in 1998. The kit includes a step-by-step information booklet, a pregnancy test, and four birth control pills. In Washington State, collaborative drug agreements between volunteer pharmacists and licensed prescribers enable pharmacists to prescribe emergency contraception pills directly--a move that is estimated to have prevented 207 unintended pregnancies and 103 abortions in less than one year. Planned Parenthood has developed two programs to increase the use of emergency contraception. The first allows clinicians to discuss emergency contraception over the phone with clients (even new ones) and to call in prescriptions to local pharmacies; the second provides women with emergency contraceptive kits to keep on hand in advance of a need for the regimen.^ieng

Finally, Japan swallows the pill.

PIP: The Health Minister, Sohei Miyashita, approved the production and sale of the low-dose oral contraceptive pill on June 16. The IUD with copper wire was also permitted. Both products will be sold in the market by Fall. Nine pharmaceutical companies filed applications for approval of manufacture and sale of pill between 1990 and 1991. Deliberations were suspended when the rate of HIV/AIDS infection increased because the pill was feared to lead a decrease in condom use. Critics also argued that it would lead to an increase in sexually transmitted diseases and unwanted side effects. The pill was defended against this charge by those who claimed that, as acquiring the pill would require a prescription, facilitating its availability would increase the number of women who would visit medical facilities and bring about a corresponding increase in the level of awareness of the dangers of infection. As to the pill¿s side effects, its defenders claimed that no other drug had been as extensively researched to reduce side effects as had the pill. Only after the drug to treat male erectile dysfunction, Viagra, had been approved did the pill regain attention. The Ministry of Health and Welfare has issued guidelines on the prescription and use of the pill in order to educate the public. What is important is that Japanese women now have the right to choose the pill as a contraceptive method. Places where they will be able to obtain the pill are also needed together with information and counseling on its use.^ieng

Emergency contraception use up -- new ECP arrives.

PIP: The first progestin-only dedicated emergency contraceptive pill (ECP) is about to enter the US market. The arrival of Plan B, a levonorgestrel-only ECP produced by the Women's Capital Corporation (WCC) of Seattle, has been long awaited by providers in the US because of it is more effective and produces fewer side effects than does the combined regimen. The WCC is taking a different marketing and distributing approach to emergency contraception than its competitor, Gynetics, focusing on existing ECP provider/dispensers such as Planned Parenthood affiliates, major Title X programs, and college/university student health centers. The FDA has also approved a change in product labeling for Gynetics¿ ECU Preven. The change, marked by the disappearance of the "Black Box Warning," puts the benefits and risks of emergency contraception in perspective, according to a Gynetics executive. It further eliminates substantial restrictions on the company's ability to communicate directly to the consumer and to the medical professional. The FDA¿s decisions should help to accelerate the process of building awareness of emergency contraception and its availability in the US.^ieng