ABSTRACT

In Argentina, new drugs can be authorized by presenting the drug’s certificate of approval in at least one of 15 countries considered to have rigorous health surveillance, without needing to carry out a local evaluation of the efficacy, safety or added therapeutic value of the new product. In this article, we evaluate the new drugs commercialized in Argentina in 2016 using different approaches: their approval by other regulatory agencies, the demonstration of their efficacy in randomized clinical trials, types of outcomes studied, rating of their added therapeutic value using two widely recognized scales, and their sale price to the public. It is concluded that, as a reflection of what occurs in developed countries, new drugs enter the market at exorbitant prices, but the majority do not represent a significant therapeutic advancements. The result is increased risks to patients and an overburdening of the public and private funding systems.

KEY WORDS:
Drug Approval; Drug Evaluation; Drug Costs; Argentina

INTRODUCTION

Every year, a huge number of new pharmaceutical products are incorporated into the market, including new formulations, new combinations or new active ingredients. A general belief exists, even among health professionals, that all new drugs offer therapeutic innovation and better results in health, and therefore strategies that accelerate and optimize patient access to these drugs are desirable.

The evaluation process of regulatory agencies generally centers on each individual drug, the efficacy and safety of which must be proven in phase III controlled clinical trials, often in comparison with a placebo. In this way, when a drug enters into the market, we know little about it in comparison with already existing products.

From a public health perspective, the value of a new drug lies in the therapeutic gain and the benefits to health for patients and for society as a whole. Diverse studies that have evaluated the clinical relevance of new drugs that have entered the market all show that the large majority do not offer any additional therapeutic benefit. According to the health authority of Canada, only 6% of the 1,147 new drugs approved between 1990 and 2003 offered substantial therapeutic advantage.¹1. Morgan SG, Bassett KL, Wright JM, Evans RG, Barer ML, Caetano PA, Black CD. “Breakthrough” drugs and growth in expenditure on prescription drugs in Canada. British Medical Journal. 2005;331(7520):815-816. Additionally, an evaluation by the National Institute for Health Care Management in the US concluded that just under 15% of the 1,035 drugs approved by the Food and Drug Administration (FDA) between 1989 and 2000 were considered truly innovative.²2. National Institute for Health Care Management. Changing Patterns of Pharmaceutical Innovation [Internet]. Washington DC: The National Institute for Health Care Management Research and Educational Foundation; 2002 [citado 12 dic 2017]. Disponible en: https://tinyurl.com/yd3rc2q8 .
https://tinyurl.com/yd3rc2q8... Analyzing the pharmaceuticals introduced in Brazil between 2003 and 2013, it was found that only 17.6% represented an "important therapeutic innovation.”³3. Botelho SF, Martins MAP, Reis AMM. Analysis of new drugs registered in Brazil in view of the Unified Health System and the disease burden. Ciência & Saúde Coletiva. 2018;23(1):215-228. The reviews from 2007 to 2016 of the journal Prescrire regarding 992 new pharmaceuticals or new uses classified only 23.3% (n=231) in one of the four categories describing some sort of benefit.⁴4. Editorial Staff. New products and new indications in 2016: a system that favours imitation over the pursuit of real progress. Prescrire International. 2017;26(182):136-139.Ward et al., using a broader take on pharmaceutical innovation, found that of the 290 drugs incorporated in the 2001-2012 period in the British National Formulary, only 26% were very innovative and 19% moderately innovative.⁵5. Ward DJ, Slade A, Genus T, Martino OI, Stevens AJ. How innovative are new drugs launched in the UK?: A retrospective study of new drugs listed in the British National Formulary (BNF) 2001-2012. BMJ Open. 2014;4(10):e006235. doi: 10.1136/bmjopen-2014-006235.
https://doi.org/10.1136/bmjopen-2014-006... In Australia, 32% (n=19) of the 59 new drugs approved between 2005 and 2007 were evaluated as having added therapeutic value.⁶6. Vitry AI, Shin NH, Vitre P. Assessment of the therapeutic value of new medicines marketed in Australia. Journal of Pharmaceutical Policy and Practice. 2013;6:2. doi: 10.1186/2052-3211-6-2.
https://doi.org/10.1186/2052-3211-6-2... Analyzing 122 new drugs authorized by the European Medicines Agency (EMA) between 1999 and 2005, van Lujin et al. found that only 10% (n=13) were better than the existing drugs in terms of their effect on clinical endpoints.⁷7. van Luijn JCF, Gribnau FWJ, Leufkens HGM. Superior efficacy of new medicines? European Journal of Clinical Pharmacology. 2010;66(5):445-448.

A good portion of these presumably new drugs are, in fact, reformulations of others whose patent is about to expire, or molecules similar to others in use that contribute little or nothing in comparison to the existing alternatives, reason for which they have come to be called "me too" drugs.

In Argentina, new drugs - that is, drugs that were never commercialized in the country - can be approved in two ways, according to Decree 150/1992.⁸8. Argentina, Poder Ejecutivo Nacional. Decreto 150/92: Normas para el registro, elaboración, fraccionamiento, prescripción, expendio, comercialización, exportación e importación de medicamentos; Ambito de aplicación; Disposiciones Generales [Internet]. 1992 [citado 01 mar 2018]. Disponible en: https://tinyurl.com/y79tdvq8 .
https://tinyurl.com/y79tdvq8... The first, and most frequent, is if the drugs have already been commercialized in at least one of the 15 countries with high-level health surveillance listed in Annex 1 of the Decree (Germany, Austria, Belgium, Canada, Helvetic Republic, Denmark, Spain, the United States, France, Italy, Israel, Japan, Netherlands, United Kingdom and Sweden), in which case it is only necessary to present the certificate of approval from those countries to the regulatory agency. In the second case, if the drug has not been previously commercialized in Argentina or in the high-level surveillance countries, the maker must offer all relevant efficacy and safety data for a full evaluation by Argentina's National Administration of Drugs, Food and Medical Technology (ANMAT).

In practice, this means that for almost the entire drug market in Argentina, the evaluation of efficacy and safety was carried out by another national agency and accepted as valid by the Argentine authorities.

Although no complete agreement or international standard exists, a number of classification systems have been developed to categorize the value of new drugs. These systems primarily seek to permit health professionals and the public access to information regarding the therapeutic value added by the new drugs in relation to the previously available options.⁹9. Ahlqvist-Rastad J, Bardelay D, Beermann B, Mignot G. Judging the therapeutic value of drugs: A comparison between La revue Prescrire and Information från Läkemedelsverket, the bulletin of the Swedish Medical Products Agency. The International Journal of Risk & Safety in Medicine. 2004;16(2):83-90.^,1010. Prescrire. Prescrire’s ratings system: new drugs and indications, at a glance [Internet]. c2018 [citado 06 mar 2018]. Disponible en: https://tinyurl.com/ydx9muqn .
https://tinyurl.com/ydx9muqn... ^,1111. Aronson JK, Ferner RE, Hughes DA. Defining rewardable innovation in drug therapy. Nature Reviews Drug Discovery. 2012;11(4):253-254.^,1212. Motola D, De Ponti F, Poluzzi E, Martini N, Rossi P, Silvani MC, Vaccheri A, Montanaro N. An update on the first decade of the European centralized procedure: how many innovative drugs? British Journal of Clinical Pharmacology. 2006;62(5):610-616.

A study that evaluated whether or not the drugs commercialized in the USA were registered, commercialized and sold at accessible prices in the Latin American countries where they were tested found great price variation among them, with Argentina being the country where the absolute prices were highest for the drugs evaluated.¹³13. Homedes N, Ugalde A. Ensayos clínicos en América Latina: implicancias para la sustentabilidad y seguridad de los mercados farmacéuticos y el bienestar de los sujetos. Salud Colectiva. 2016;12(3):317-345.

The objective of this study is to evaluate the therapeutic value of the new drugs approved by ANMAT during the year 2016 and estimate the monthly cost of treatment.

METHODS

We identified the drugs approved by ANMAT for commercialization in Argentina during the year 2016, consulting the new medicines approved for use with or without prescription published monthly on ANMAT's website.¹⁴14. Administración Nacional de Medicamentos, Alimentos y Tecnología Médica. Altas en el vademécum nacional de medicamentos [Internet]. c2018 [citado 01 mar 2018]. Disponible en: https://tinyurl.com/y8rb5wog .
https://tinyurl.com/y8rb5wog... When a single active ingredient had two dosage forms, they were analyzed separately. The following products were excluded from the study: drugs used for diagnosis, including radiological contrasts; hydroelectrolitic, nutritional and irrigation solutions; products related to hemodialysis; and vaccines and immunoglobulins.

According to the composition, each medicine was classified as a monodrug or a fixed-dose combination drug. The corresponding World Health Organization's Anatomical Therapeutic Chemical (ATC) code was assigned, as indicated in the label authorized by ANMAT or utilizing the WHO Collaborative Centre for Drug Statistics Methodology database, in accordance with the established instructions.¹⁵15. WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index 2018 [Internet]. c2017 [citado 01 mar 2018]. Disponible en: https://tinyurl.com/yckuy4rt .
https://tinyurl.com/yckuy4rt...

We classified each drug authorized in 2016 as previously commercialized in Argentina if there was at least one product with the same active ingredients and route of administration in the commercial pharmaceutical catalog in January 2016,¹⁶16. Kairos. 2016;XXXVIII(448):1-210. and as a new drug (ND) in the remaining cases. These NDs correspond to new active ingredients, new combinations of active ingredients, or a new route of administration for an already existing active ingredient. The different packaging of drugs with the same active ingredients and routes of administration were considered to be a single ND in this analysis. We identified the indications for each ND according to the label authorized by ANMAT.

To evaluate the therapeutic value of the NDs four different approaches were used: the approval by other regulatory agencies, the demonstration of their efficacy in randomized clinical trials and types of endpoints studied, the rating provided by the journal Prescrire and the application of the therapeutic value scale developed by Ahlqvist-Rastad et al.

It was established whether or not the NDs were authorized by the FDA,¹⁷17. Drugs@FDA: FDA Approved Drug Products [Internet]. c2018 [citado 01 mar 2018]. Disponible en: https://tinyurl.com/l5mfqlh .
https://tinyurl.com/l5mfqlh... and the date of approval, the priority assigned to the drug¹⁸18. Center for Drug Evaluation and Research. Manual of policies and procedures [Internet]. 2013 [citado 01 mar 2018]. Disponible en: https://tinyurl.com/yamw8h6s .
https://tinyurl.com/yamw8h6s... and the state of the drug as treatment for "neglected" or "orphan" diseases were noted. A drug review is "priority" for the FDA when the preliminary review indicates that the drug treats a serious or life-threatening condition and, if approved, would be a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious or life-threatening condition compared to available therapies; the review is "standard" in all other cases. If was also established whether the drug was approved by the EMA,¹⁹19. European Medicines Agency [Internet]. c1995-2018 [citado 01 mar 2018]. Disponible en: https://www.ema.europa.eu/ .
https://www.ema.europa.eu/... which regulates the commercialization of new drugs in the European Union. When the ND were not approved by the FDA nor by the EMA, it was established whether they were authorized by the other countries included in the Decree 150/92⁸8. Argentina, Poder Ejecutivo Nacional. Decreto 150/92: Normas para el registro, elaboración, fraccionamiento, prescripción, expendio, comercialización, exportación e importación de medicamentos; Ambito de aplicación; Disposiciones Generales [Internet]. 1992 [citado 01 mar 2018]. Disponible en: https://tinyurl.com/y79tdvq8 .
https://tinyurl.com/y79tdvq8... or whether the ANMAT had performed an independent evaluation. In the latter case, the corresponding ANMAT file was consulted to identify the evaluation criteria utilized.

In the second phase, randomized clinical trials showing the efficacy of the ND were identified, based on those described in the labels authorized by the FDA and/or ANMAT; if none were described, a search was carried out in PubMed using the name of the active ingredient and the filter for type of article set to “randomized controlled trial.” It was considered that a ND has demonstrated efficacy in four situations: 1) when at least one randomized clinical trial shows efficacy for the indication authorized by ANMAT; 2) in the combinations of drugs, if at least one randomized clinical trial shows the efficacy of the coadministered individual components and the bioequivalence of the combination is shown; 3) for new formulations of a drug, when the efficacy of the previous formulation is demonstrated by randomized clinical trials and the bioequivalence of the new formulation is demonstrated; and 4) "drugs with obvious efficacy," defined as those that, even without randomized clinical trials for efficacy, are considered to have high intrinsic value due to their immediate and obvious benefits in uncontrolled studies.²⁰20. Laporte JR, Porta M, Capella D. Drug utilization studies: a tool for determining the effectiveness of drug use. British Journal of Clinical Pharmacology. 1983;16(3):301-304. It was noted if the efficacy had been demonstrated for clinically relevant variables, validated surrogate variables - those for which there is strong evidence that modification predicts a specific clinical benefit - or only for other surrogate variables.²¹21. United States, Food and Drug Administration. New drug, antibiotic, and biological drug product regulations: accelerated approval; Final rule. Federal Register. 1992;57(239):58942-58960.^,2222. FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Silver Spring: Food and Drug Administration; 2016 [citado 05 mar 2018]. Disponible en: https://tinyurl.com/ydbcc2er .
https://tinyurl.com/ydbcc2er... ^,2323. Twaddell S. Surrogate outcome markers in research and clinical practice. Australian Prescriber. 2009;32(2):47-50.^,2424. Kim C, Prasad V. Cancer drugs approved on the basis of a surrogate end point and subsequent overall survival: an analysis of 5 years of US food and drug administration approvals. JAMA Internal Medicine. 2015;175(12):1992-1994.^,2525. Rupp T, Zuckerman D. Quality of life, overall survival, and costs of cancer drugs approved based on surrogate endpoints. JAMA Internal Medicine. 2017;177(2):276-277.

In the third phase, the classification assigned to the new drug by the journal Prescrire, an independent French publication that evaluates the new authorized drugs to rate the degree of therapeutic progress, tangible to the patient, that a ND contributes for a concrete indication, positing the benefit/risk balance of the drug in relation to other available therapeutic alternatives.¹⁰10. Prescrire. Prescrire’s ratings system: new drugs and indications, at a glance [Internet]. c2018 [citado 06 mar 2018]. Disponible en: https://tinyurl.com/ydx9muqn .
https://tinyurl.com/ydx9muqn... When the drug has a number of indications, the Prescrire rating may be different for each of them. In such cases, the best rating among the indications authorized by the ANMAT were used.

Lastly, based on all the information obtained, two of the authors independently applied the therapeutic value evaluation scale developed by Ahlqvist-Rastad et al., that emphasized the degree of novelty of the drug given the previously available options⁹9. Ahlqvist-Rastad J, Bardelay D, Beermann B, Mignot G. Judging the therapeutic value of drugs: A comparison between La revue Prescrire and Information från Läkemedelsverket, the bulletin of the Swedish Medical Products Agency. The International Journal of Risk & Safety in Medicine. 2004;16(2):83-90.⁾ (Table 1). The agreement among the observers was evaluated with Cohen's kappa coefficient and the discrepancies were resolved by consensus.

As none of the classifications utilized up to this point have considered the cost of the drugs, this aspect was incorporated utilizing the sales price to the public published in the commercial drug catalog Kairos at the time the drug appeared on the market, and was expressed in US dollars according to the exchange rate for that date. For medications for chronic use, a monthly treatment price was estimated using the daily dose defined by the WHO Collaborative Centre for Drug Statistics Methodology.¹⁵15. WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index 2018 [Internet]. c2017 [citado 01 mar 2018]. Disponible en: https://tinyurl.com/yckuy4rt .
https://tinyurl.com/yckuy4rt... For those cases in which a daily dose was not established, the dosage recommended in the ANMAT-authorized label was utilized, and if this information was lacking, the dosage from the FDA label was utilized. For drugs used sporadically, the sales price of one packaged unit was recorded. For dantrolene, which is only commercialized for hospital use, the average number of vials needed per episode of malignant hyperthermia was calculated, according to the ANMAT-authorized label.

RESULTS

Between 01/01/2016 and 12/31/2016, the ANMAT authorized 825 drugs, of which 10% (n=82) correspond to a ND. In 79 cases the approval was for a new active ingredient (or a new combination of active ingredients) and in the other three cases, for a new administration route for an active ingredient already in the market.

We excluded from the analysis products used for diagnosis (n=2) and an irrigation solution (n=1). After counting as a single drug the different packaging of new drugs (with the same active ingredients and administration routes), the list was reduced to 45 ND incorporated into the Argentine market in 2016. These are presented, along with the authorized indications, according to the ATC classification order (Table 2). All NDs were authorized as prescription drug products.

Almost a third of the NDs (31%, n=14) were combinations of more than one active ingredient. The antineoplastic and immunomodulatory drugs were the therapeutic class with the greatest number of new drugs (33%, n=15, including five monoclonal antibodies and six tyrosine kinase inhibitors), followed by antiinfective drugs (13%, n=6) (Figure 1).

Approval by other regulatory agencies

The majority of the NDs approved by ANMAT in 2016 had been previously authorized by the FDA (80%, n=36) and the EMA (78%, n=35). Of the six ND that were not authorized by either of these two agencies, four had approval in countries listed in the Annex I of Decree 150/92 (carbetocin, hydroquinone, rosuvastatin + ezetimibe, and citrulline malate) and the remaining two were evaluated directly by ANMAT (hyaluronic acid + lidocaine for intra-joint use and choline salicylate + benzocaine as a topical oral treatment). Of the 36 NDs approved by the FDA, 53% (n=19) qualified for priority review and 42% (n=15) were for orphan diseases.

Drugs evaluated directly by ANMAT

The criteria identified in the two original evaluations carried out by ANMAT were diverse. In the case of choline salicylate and benzocaine for topical oral treatment, the approval was based on the efficacy and safety of the individual components, without reference to studies that evaluated the fixed-dose combination.²⁶26. Administración Nacional de Medicamentos, Alimentos y Tecnología Médica. Disposición 8806/16 [Internet]. 2016 [citado 01 mar 2018]. Disponible en: https://tinyurl.com/y7gfs6kv .
https://tinyurl.com/y7gfs6kv... ⁾ Regarding hyaluronic acid and lidocaine for intra-joint use, it was framed as a new use of the previously approved hyaluronic acid, and not as a new drug.²⁷27. Administración Nacional de Medicamentos, Alimentos y Tecnología Médica. Disposición 0759/16 [Internet]. 2016 [citado 01 mar 2018]. Disponible en: https://tinyurl.com/y7u7ejug .
https://tinyurl.com/y7u7ejug...

Proven efficacy in randomized controlled trials

For 62% of the ND (n=28), randomized controlled trials were found that demonstrated efficacy; another 20% (n=9) were new combinations or formulations of drugs that already had randomized clinical trials showing efficacy, in which case the bioequivalency was all that was demonstrated in order for the new preparation to be approved (Table 3).

Of the 18% of ND (n=8) without randomized clinical trials for efficacy, 4% (n=2) can be categorized as drugs "with obvious efficacy," that is, dantrolene for malignant hyperthermia and nitisinone in hereditary tyrosinemia. The remaining 13% (n=6) did not have randomized clinical trials for efficacy; two of these, antineoplastic drugs, were evaluated in uncontrolled trials.

The second aspect to be evaluated was whether there was proven efficacy for clinically relevant endpoints or for surrogate endpoints (validated or not validated). Of the NDs, 44% (n=20) showed efficacy in relevant endpoints; another 22% (n=10) were effective in validated surrogate variables: forced expiratory volume in the first second (FEV1) for Chronic Obstructive Pulmonary Disease (EPOC), ⁽²⁸28. Esteban C, Quintana JM, Aburto M, Moraza J, Egurrola M, España PP, Pérez-Izquierdo J, Capelastegui A. Predictors of mortality in patients with stable COPD. Journal of General Internal Medicine. 2008;23(11):1829-1834.^,2929. Traver GA, Cline MG, Burrows B. Predictors of mortality in chronic obstructive pulmonary disease: A 15-year follow-up study. The American Review of Respiratory Disease. 1979;119(6):895-902. undetectable viral load in HIV drugs,²²22. FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Silver Spring: Food and Drug Administration; 2016 [citado 05 mar 2018]. Disponible en: https://tinyurl.com/ydbcc2er .
https://tinyurl.com/ydbcc2er... sustained virologic response for hepatitis C, ⁽³⁰30. Mishra P, Murray J, Birnkrant D. Direct-acting antiviral drug approvals for treatment of chronic hepatitis C virus infection: Scientific and regulatory approaches to clinical trial designs. Hepatology: Official Journal of the American Association for the Study of Liver Diseases. 2015;62(4):1298-1303.^,3131. van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour J-F, Lammert F, Duarte-Rojo A, Heathcote EJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308(24):2584-2593. reduction in low-density lipoproteins (LDL) in hyperlipidemia,²²22. FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Silver Spring: Food and Drug Administration; 2016 [citado 05 mar 2018]. Disponible en: https://tinyurl.com/ydbcc2er .
https://tinyurl.com/ydbcc2er... and intraocular pressure in glaucoma treatment.²³23. Twaddell S. Surrogate outcome markers in research and clinical practice. Australian Prescriber. 2009;32(2):47-50. Among the authorized NDs, 24% (n=11) showed efficacy only in non-validated surrogate variables and 9% (n=4) had no proof of efficacy. These results are described in Table 3 and summarized in Table 4.

Classification assigned by the journal Prescrire

Of the 45 ND authorized in 2016, 39 were evaluated in the journal Prescrire. More than 70% of these did not offer advantages: the category encompassing the greatest number of drugs was “nothing new” (41%, n=16), with another 26% (n=10) classified as “not acceptable” and 5% (n=2) as “judgment reserved”. Only 28% of the ND evaluated by Prescrire (n=11) were classified in categories that represent a minimum advance with respect to the previous therapeutic options (Table 5).

Evaluation of therapeutic value

There was good interobserver agreement in assigning therapeutic value to the NDs (?αμπ;#922=0,90). The evaluation, according to the scale of Ahlqvist-Rastadet al., shows that the majority of the ND (51%, n=23) do not have added therapeutic value (category C), another 9% (n=4) are considered inferior to the existing alternatives (category D) and 18% (n=8) have uncertain therapeutic value (E). Only 22% (n=10) of the ND represent some degree of added therapeutic value (categories A and B) (Figure 2 and Table 3).

Sale price to the public of the new drugs

Of the 45 NDs authorized, there were five for sporadic use and 40 for chronic use. In 20 of the chronic use drugs, the monthly price of the defined daily dose was calculated; in another 17 the dose from the ANMAT label was used, and in one the dose from the FDA label was used. There were two products (hydroquinone and nitisinone) for which it was not possible to obtain the sales price.

The treatment price of the new drugs for chronic use shows great dispersion, from $13 to $56,516 per month (in US dollars). The price of most drugs was elevated, with an average price of $7,974 and a median of $5,849 (interquartile range: Q1=$172; Q3=$14,284). For the NDs with added therapeutic value, the price was even more elevated, with an average price of $13,800 (median=$13,821; interquartile range: Q1=$5,021; Q3=$13,325).

When grouping the drugs by primary indication, their concentration into different price ranges according to the pathology treated can be observed (Figure 3). It can also be observed that the monthly price of treatment for the 14 drugs for oncological use goes from $3,000 to $56,000, with an average of $17,700. To contrast this information, only five of these drugs had added therapeutic value, five had similar therapeutic value to existing drugs, three had unknown therapeutic value and one was considered inferior to existing alternatives.

DISCUSSION

This study found that, in the year 2016, 45 NDs were incorporated into the Argentine market, the majority of which were previously approved by the FDA and the EMA. Of these NDs, 13% did not have randomized clinical trials demonstrating efficacy and 24% had demonstrated efficacy only for non-validated surrogate variables. In terms of therapeutic value, 72% of the NDs did not represent significant advances according to the evaluation of the journal Prescrire and 78% did not add therapeutic value according to the classification of Ahlqvist-Rastad et al. For the two drugs evaluated only by ANMAT, the approval criteria used were not robust. In addition, the price of the drugs was substantial, with a median of $5,849 per month for chronic use drugs. Only one out of every 4 NDs represented a therapeutic advance and almost all are sold at practically inaccessible prices.

These results are in agreement with those obtained in the previously cited studies. The studies carried out in different parts of Latin America and the world all show an absence of added therapeutic value of the majority of the new drugs that are commercialized. In synthesis, in the best case scenario, only a quarter of these drugs represents some type of improvement in the existing therapeutic options.

The value of these drugs can be analyzed using two different but complementary approaches. The first contemplates the pharmaceutical innovation and evaluates, for example, the novelty of the chemical structure, the molecular target, the action mechanism, the drug class, the synthesis method or the drug formulation.¹¹11. Aronson JK, Ferner RE, Hughes DA. Defining rewardable innovation in drug therapy. Nature Reviews Drug Discovery. 2012;11(4):253-254.^,1212. Motola D, De Ponti F, Poluzzi E, Martini N, Rossi P, Silvani MC, Vaccheri A, Montanaro N. An update on the first decade of the European centralized procedure: how many innovative drugs? British Journal of Clinical Pharmacology. 2006;62(5):610-616. The second focus privileges the degree to which the new drug represents an added therapeutic value with respect to the previously available options, that is, its concrete additional benefit for patients.⁹9. Ahlqvist-Rastad J, Bardelay D, Beermann B, Mignot G. Judging the therapeutic value of drugs: A comparison between La revue Prescrire and Information från Läkemedelsverket, the bulletin of the Swedish Medical Products Agency. The International Journal of Risk & Safety in Medicine. 2004;16(2):83-90.^,1010. Prescrire. Prescrire’s ratings system: new drugs and indications, at a glance [Internet]. c2018 [citado 06 mar 2018]. Disponible en: https://tinyurl.com/ydx9muqn .
https://tinyurl.com/ydx9muqn... With the first focus, applied by regulatory agencies, a drug that is more effective than a placebo can be considered innovative, however with the second criteria, which is stricter and has greater public health relevance, it is necessary to demonstrate benefit in clinical trials as compared to the best available alternative.

A number of studies have compared the new therapeutic agents registered by the FDA, the EMA and other regulatory agencies. Although no significant differences were found for the marketed new drugs, a recent study observed that the indications approved by the FDA, the EMA and the Swiss agency Swissmedic (SMC) for the same drugs differed in content in 76.9% of cases.³³33. Zeukeng MJ, Seoane-Vazquez E, Bonnabry P. A comparison of new drugs approved by the FDA, the EMA, and Swissmedic: an assessment of the international harmonization of drugs. European Journal of Clinical Pharmacology. 2018;74(6):811-818. It is clear that discrepancies among regulatory agencies are not only based on the evidence, but also cultural, political and economic factors as well as the characteristics of each health care system.³⁴34. Braillon A. The race for drug approvals: hasten slowly? European Journal of Clinical Pharmacology. 2018;74(9):1197-1198.

Although the FDA’s designation of different categories such as “priority review” or “orphan drug” appears to promote stricter innovation criteria, in practice there are so many drugs classified as priority that the term loses specificity and becomes indiscriminate. Regarding the orphan diseases investigated, these are usually genetic syndromes or oncological variants with a very low prevalence in the USA, and not infectious diseases of high prevalence in developing countries, for which there are no effective therapeutic alternatives.

The therapeutic value of a ND is even less certain when, using the “accelerated approval” route established by regulatory agencies, the drug appears on the market with demonstrated efficacy only for non-validated surrogate variables or even without controlled trials. Examples of these questioned surrogate variables include the six-minute walk test for pulmonary arterial hypertension³²32. Gabler NB, French B, Strom BL, Palevsky HI, Taichman DB, Kawut SM, Halpern SD. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation. 2012;126(3):349-356. and many of the habitual endpoints of oncological drug studies.³⁵35. Prasad V, Kim C, Burotto M, Vandross A. The strength of association between surrogate end points and survival in oncology: A systematic review of trial-level meta-analyses. JAMA Internal Medicine. 2015;175(8):1389-1398. The post-commercialization studies required by regulatory agencies to complete this information exceed the stipulated time frame and often do not contribute the expected information regarding clinically relevant endpoints.²⁴24. Kim C, Prasad V. Cancer drugs approved on the basis of a surrogate end point and subsequent overall survival: an analysis of 5 years of US food and drug administration approvals. JAMA Internal Medicine. 2015;175(12):1992-1994.^,2525. Rupp T, Zuckerman D. Quality of life, overall survival, and costs of cancer drugs approved based on surrogate endpoints. JAMA Internal Medicine. 2017;177(2):276-277.^,3636. Pease AM, Krumholz HM, Downing NS, Aminawung JA, Shah ND, Ross JS. Postapproval studies of drugs initially approved by the FDA on the basis of limited evidence: systematic review. BMJ: British Medical Journal. 2017;357:j1680. doi: 10.1136/bmj.j1680.
https://doi.org/10.1136/bmj.j1680... ^,3737. Naci H, Smalley KR, Kesselheim AS. Characteristics of preapproval and postapproval studies for drugs granted accelerated approval by the Us Food and Drug Administration. JAMA. 2017;318(7):626-636.^,3838. Knopf K, Baum M, Shimp WS, Bennett CL, Faith D, Fishman ML, Hrushesky WJ. Interpretation of surrogate endpoints in the era of the 21st Century Cures Act. BMJ: British Medical Journal. 2016;355:i6286. doi: 10.1136/bmj.i6286.
https://doi.org/10.1136/bmj.i6286... ^,3939. Gellad WF, Kesselheim AS. Accelerated approval and expensive drugs: A challenging combination. The New England Journal of Medicine. 2017;376(21):2001-2004.^,4040. Hawkes N. German body calls for pause in European plan for fast track drug approval. BMJ. 2016;354:i4479. doi: 10.1136/bmj.i4479.
https://doi.org/10.1136/bmj.i4479....

The result of this lax form of drug approval is the incorporation of products with unproven efficacy and safety in clinically relevant variables, with preliminary safety information and, in general, a price that stresses the viability of funding mechanisms.

The legal framework in Argentina, which permits the inscription of any drug approved by the regulatory agencies in developed countries,⁸8. Argentina, Poder Ejecutivo Nacional. Decreto 150/92: Normas para el registro, elaboración, fraccionamiento, prescripción, expendio, comercialización, exportación e importación de medicamentos; Ambito de aplicación; Disposiciones Generales [Internet]. 1992 [citado 01 mar 2018]. Disponible en: https://tinyurl.com/y79tdvq8 .
https://tinyurl.com/y79tdvq8... reproduces locally the same problems. Bills exist to create an agency for the evaluation of health technologies that could intervene in the incorporation of new drugs into the social security system. It is crucial that in these types of decisions, standards be used that consider the added therapeutic value of a new drug, in addition to the analysis of cost-effectiveness in comparison with the alternatives.

However, the results of the analyzed studies suggest that to respond to the local health priorities larger changes are necessary in the legal framework, abandoning the automatic inscription of drugs approved by the regulatory agencies of other countries. The new form of inscription should include an independent evaluation of the new drugs and approve the entry into the local market of those drugs that represent true advances.

As an example of interventions of this type in other Latin American countries, a recent decree in Colombia establishes that the inscription of new drugs is dependent on an evaluation of their therapeutic value in relation to a selected comparison, along with an economic evaluation, that could include an analysis of cost-effectiveness as well as the budget impact.⁴¹41. Colombia, Ministerio de Salud. Decreto 433 de 2018 [Internet]. 2018 [citado 15 mar 2018]. Disponible en: https://tinyurl.com/y78xoxz2 .
https://tinyurl.com/y78xoxz2... In this way, the evaluation of the therapeutic value and the establishment of the price occur prior to the drug entering the local market.

CONCLUSIONS

As a mirror of what occurs in developed countries, only a minor fraction of the new drugs approved in Argentina in 2016 represented a significant therapeutic advance. Nevertheless, the majority had a very elevated price. The result is an increase in risks to patients who are exposed to drugs without proven clinical efficacy and an overburdening of public and private funding systems. To improve these results, an evaluation of the therapeutic value and the price of the drug should be incorporated as a requirement for the authorization of the inscription of new drugs in Argentina, or at least be a step to authorize their inclusion in the social security system.

ACKNOWLEDGEMENTS

We thank the editors of the journal Prescrire for providing us free access to the journal’s articles.

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