3783 The tale of lenalidomide clinical superiority over thalidomide and regulatory and cost-effectiveness issues A narrativa de que a lenalidomida é clinicamente superior à talidomida, e questões regulatórias e de custo-efetividade Resumo A Agência Nacional de Vigilância Sani- tária (ANVISA) aprovou em abril de 2017 a lena- lidomida (LEN) para o mieloma múltiplo (MM) e síndrome mielodisplásica. A ANVISA havia ne- gado o registro em 2010, e indeferido um recurso apresentado em 2012. O motivo do indeferimento foi a falta de estudos comparativos de efetividade demonstrando que LEN era mais eficaz do que a talidomida (TAL), um medicamento rigorosa- mente controlado pela lei federal 10.651/2003 e dispensado gratuitamente a pacientes através de unidades de saúde e hospitais públicos. O recuo não explicado da ANVISA em relação ao registro da LEN foi um inquestionável triunfo do lobby que sucedeu a recusa inicial do registro, a frente do qual estavam políticos, membros do Congres- so, associações de pacientes e sociedades médicas. Dois ensaios randomizados (fase III) e três estudos observacionais (caso-controle e coorte de base po- pulacional) compararam a efetividade de terapias para o MM com TAL- e com LEN. Em conjunto, esses estudos mostraram que não havia diferen- ças quanto a eficácia de tratamentos com LEN- e aqueles com TAL. A LEN causou menos neuropa- tias, e efeitos adversos hematológicos mais graves. Ela é muito mais cara do que a TAL, e a substitui- ção da TAL pela LEN aumentará muito os custos da assistência pública à saúde no Brasil. Palavras-chave Mieloma múltiplo, Custo-efeti- vidade, Câncer, Custos da assistência médica. Abstract In April 2017, the National Sanitary Surveillance Agency (ANVISA-Brazil) approved lenalidomide (LEN) for multiple myeloma (MM) and myelodysplastic syndrome. ANVISA had re- jected the first application in 2010, and denied a request for reconsideration in 2012. The reason for rejection was the lack of comparative effectiveness studies proving that LEN was more effective than thalidomide (THAL), a strictly controlled drug regulated by Federal law 10.651/2003 and dispen- sed to patients (at no costs) through public health system units and hospitals. ANVISA unexplained retreat on the LEN approval for marketing was an unquestionable triumph of the lobbying that ensued the denial, at the forefront of which were politicians, Congress members, patient organi- zations and medical societies. Two randomized (phase III) trials and three observational (case- control and population-based cohort) compared the effectiveness of THAL- versus LEN-based the- rapies in MM. Overall, these studies showed no difference in efficacy between LEN- and THAL -based therapies. LEN caused less neuropathy, and more severe hematologic adverse effects. It is much costlier than THAL, and substitution of THAL by LEN shall raise considerably public he- althcare costs in Brazil. Keywords Multiple myeloma, Cost-effectiveness, Cancer, Healthcare costs. Francisco José Roma Paumgartten (http://orcid.org/0000-0002-6207-0149) 1 DOI: 10.1590/1413-812320182410.28522017 1 Escola Nacional de Saúde Pública, Fiocruz. Av. Brasil 4036/913, Manguinhos. 21040-361 Rio de Janeiro RJ Brasil. paum@ensp. fiocruz.br T e m A s l iv R e s f R e e T h e m e s 3 7 8 4 P au m ga rt te n F JR introduction To grant marketing approval for a new medicine, a regulatory agency demands that the applicant presents evidence of its efficacy and safety for intended clinical uses. Along this line, the best empiric evidence that a drug is effective and safe, or that potential therapeutic benefits outweigh risks of harm to patients, is generally provided by good quality phase III randomized clinical trials (RCTs) controlled with a placebo, or with a ther- apy of proven effectiveness (active comparator), whenever the use of an inactive comparator is considered unethical. The US FDA, EMA and most national regu- latory agencies, however, do not require data on comparative effectiveness and safety, or evidence that a new drug is clinically superior to existing therapies. It follows that a newly approved drug is not necessarily better than preceding ones, and thus it may not add to existing therapies. This ap- plies, for instance, to drugs called in pharmaceu- tical jargon terms “me-too” or “follow-on” drugs, or medicines sharing with a drug already on the market a similar chemical structure, an identical mechanism of action and the same therapeutic indications1. In other words, “me-too” drugs are not truly innovative or breakthrough medicines developed to treat a morbid condition; rather they are just “more of the same”, or similar drugs that are not clinically superior to a pioneering one. “Me-too” medicines may be the outcome of a frustrated attempt to increase efficacy and or to attenuate the toxicity of a prototype drug by altering its molecule, or otherwise be a delib- erate imitation of a pioneer medicinal product. Some authors believe that “me-too”s are wasteful duplications and propose that agencies’ require- ments for approving a new drug should be not only the evidence that it is effective and safe, but also a demonstration that it is clinically superi- or to pre-existing therapies. Others, however, are against imposing regulatory obstacles to the development of non-innovative and “me-too” drugs arguing that they enhance competition within the pharmaceutical market and, by doing so, they stimulate lowering prices what ultimate- ly expands the access of low-income people to medicines1,2. The National Sanitary Surveillance Agency (ANVISA-Brazil) policy for “me-too” drugs was made explicit in a comment posted on its web- site: …it is difficult or even impossible to classify a (new) medicine as a “me-too” drug on the occasion it is (first) registered because some of its attributes that would allow us to make this classification can only be (fully) assessed after the product is market- ed and used in large scale”, and “...current Brazil- ian laws do not support denying registration of new drugs based on such argument. For the foregoing reasons, according to ANVISA’s note, the agency does not necessarily reject applications of “me- too” drugs even if they, apparently, do not add to existing therapies2. A major problem with non-innovative drugs is that pharmaceutical companies generally do not fairly and adequately inform doctors and consumers about the degree of similarity be- tween new products and pre-existing ones. To boost sales of a new drug, companies almost invariably claim that their products are in some way better than preceding ones, even when this allegation is unsupported by comparative effec- tiveness (and safety) research data. A common allegation, for instance, is that it might be ben- eficial for a subgroup of patients who do not re- spond satisfactorily to similar drugs already on the market. In many cases, however, this claim is at best an untested - and self-regarding–hypoth- esis2. The hypothetical subpopulation of patients (who would respond differently to a new drug) is seldom, if ever, characterized by controlled clin- ical studies. Lenalidomide, a teratogenic thalidomide-like drug (Figure 1), challenged Anvisa’s viewpoint on “me-too” products, and rekindled the debate on whether the agency should require the appli- cant a proof of clinical superiority over existing therapies for granting a marketing approval for some drugs. A demand for comparative effective- ness research data are of utmost importance, for instance, if estimated costs of treatment with the new drug are much higher than the costs of ther- apies with drugs already available on the market. This article appraises critically the available evidence on the comparative effectiveness of lenalidomide- versus thalidomide-based thera- pies for MM, and regulatory and cost-effective- ness issues behind lenalidomide authorization for sales in Brazil. methods The approval of lenalidomide for sales in Brazil is discussed here as an exploratory case study. It brings us to question ANVISA’s regulatory policy for non-innovative (me-too) drugs, par- ticularly when the new product compares un- favorably with its prototype medicine in terms 3 7 8 5 C iên cia & Saú d e C o letiva, 2 4 (1 0 ):3 7 8 3 -3 7 9 2 , 2 0 1 9 figure 1. Lenalidomide resulted from two minor alterations in the phthalimide ring of thalidomide (indicated by circles). It is more potent than thalidomide (therapeutic doses: 15-25 mg/day versus 100-200 mg/day, respectively). Comparative effectiveness research, however, showed that they have nearly the same effectiveness in the treatment of multiple myeloma. Nonetheless, lenalidomide, compared with its prototype drug, was associated with a lower incidence of neuropathy and a higher occurrence of severe hematologic side effects. of cost-effectiveness. Nonetheless, this case also involves another unique regulatory issue. Owing to its teratogenicity and the fact that the coun- try has world’s greatest number of thalidomide victims born after 1965 (i.e., “avoidable cases” of thalidomide birth defects), it is the only drug regulated by a specific Federal law in Brazil. The law 10.651/2003 forbids thalidomide sales, and further agency-issued regulations impose addi- tional constraints to prescription and dispensing. Since the law makes no provision for thalidomide analogs such as lenalidomide, Brazil has clearly adopted a regulatory double standard for thalid- omide and thalidomide-like teratogens marketed by pharmaceutical companies. A thorough search was conducted in biomedical electronic databas- es (Medline/Pubmed, BVS Brazil/Bireme, http:// www.brasil.bvs.br), to identify comparative effec- tiveness and safety studies of thalidomide versus lenalidomide for treatment of multiple myeloma and or myelodysplastic syndrome (MDS). A sim- ilar search was undertaken to find comparative cost-effectiveness studies of thalidomide-versus lenalidomide-based therapies for MM and MDS. Searches in Medline and BVS Brazil/Bireme da- tabases were conducted using a variety of search- ing strings (e.g., “lenalidomide AND thalidomide AND comparative effectiveness”; “lenalidomide AND thalidomide AND multiple myeloma AND effectiveness”; “thalidomide AND myeloma AND effectiveness AND safety”; and others), and cov- ered a time window between database inception and October 31st, 2017. Reference lists of articles and documents were examined to find any ad- ditional relevant study. Furthermore, the author went over the Virtual Library on Health of the Brazilian Ministry of Health website (BVS MS, www.bvsms.saude.gov.br/index.php), and the Brazilian Sanitary Surveillance Agency (Anvisa) compilation of legislation on health products to identify all regulations and laws potentially ap- plicable to this regulatory drug topic. Results and Discussion Brief regulatory history of thalidomide and lenalidomide in the Us and Brazil Owing to its teratogenicity, and because prev- alence of Hansen disease is almost negligible in the country, thalidomide was not approved for sale in the US until 1998 when, in an attempt to put an end to smuggling and uncontrolled use of the drug for a variety of medical conditions, the US FDA approved it. Curiously, the first au- thorized therapeutic indication for thalidomide (Thalomid® made by Celgene® Co) was erythema nodosum leprosum (ENL), or type-2 reaction, a medical condition extremely rare, or even non- existent in the US. Only a few years later, in May 2006, FDA granted accelerated approval for tha- lidomide (in combination with dexamethasone) for the treatment of newly diagnosed multiple myeloma (MM) patients. The German company Chemie Grünenthal GmbH had launched thalid- omide in 1957, and thus it has no longer patent protection. Nonetheless, a patent was granted to Celgene® Co for its System for Thalidomide Edu- cation and Prescribing Safety (STEPS® Program, a restricted distribution system intended to pre- vent thalidomide use by pregnant women) what means in practice that Thalomid® has a market- ing exclusivity in the US3. Lenalidomide (Revlimid®) was the first tha- lidomide-like drug obtaining a marketing autho- rization (Figure 1). It was developed by Celgene® Co and approved by the FDA for treatment of myelodysplastic syndrome (MDS) and multiple myeloma (MM) in 2005 (December) and 2008, respectively. The European Medicines Agency (EMA), on the other hand, granted a marketing authorization for lenalidomide use in MM (in combination with dexamethasone for patients who had received at least one prior therapy), in Thalidomide Lenalidomide Phthalimide ring Glutarimide ring 3 7 8 6 P au m ga rt te n F JR 2007, and for use in MDS, in 2013. In the EU and US, the approved indications for lenalidomide were further expanded to include previously un- treated MM patients who were not eligible for transplants, monotherapy for the maintenance treatment of patients with newly diagnosed MM (after autologous stem cell transplantation), and for therapy of mantle cell lymphoma in patients whose disease had relapsed, or progressed after two prior therapies. Lenalidomide costs near- ly US $163,381 per year for the average patient4 and thus lenalidomide-based therapies are much costlier than thalidomide-based treatments for MM. Both FDA and EMA awarded an orphan drug status/designation to lenalidomide because of the rarity of multiple myeloma. Data from the National Cancer Institute (NCI) informs that, in the US, the incidence (new cases) of MM was 6.6 per 100,000 men and women per year, and that, in 2014, there were estimated 118,539 people liv- ing with MM in the country5. Notwithstanding the “orphan drug” status, lenalidomide (Revlim- id®) proved to be a highly profitable product. It was Celgene® Co’s blockbuster drug with sales in the first 2017 quarter of US$ 1,884 million against US$ 26 million for Thalomid® in the same period6. In 2008, Zodiac® Co (a company licensed by Celgene® Co to sell Revlimid® in Brazil) filed an application for lenalidomide use in MM and MDS that the Brazilian agency ANVISA reject- ed in 2010. The rejection was based on a re- port by the Advisory Committee on Medicines (CATEME) whose members pointed out that the applicant provided no evidence that lenalid- omide was more effective and or safer than tha- lidomide for both therapeutic indications. On the understanding that, similarly to thalidomide, lenalidomide also proved to be a strong teratogen in non-human primates, and that it is much more expensive than its prototype drug, CATEME rec- ommended that the applicant should provide sound evidence that lenalidomide is clinically superior to thalidomide (to be demonstrated by comparative effectiveness research data) before a marketing authorization is granted. The negative decision was followed by a powerful lobbying at the forefront of which were patient organiza- tions, medical specialty societies, politicians and Congress members. In 2012, ANVISA’s board of directors denied a request for reconsideration filed by Zodiac® Co thereby confirming the appli- cation rejection. In April 2017, ANVISA ignored all the reasons for the first application rejection and, in an unexplained retreat, approved lenalid- omide registration in the country. Nonetheless, the publication of the positive decision on regis- tration, that ultimately enacts the authorization for sales, still depends on a special regulation on the control of its use and dispensing to be issued by the agency7. Comparative effectiveness of lenalidomide and thalidomide in the treatment of multiple myeloma Thalidomide The notion that antiangiogenic compounds could be useful to treat some types of cancer stands on the observation that solid tumors re- quired neovascularization (angiogenesis) for growth and survival7. In 1994, D’Amato et al. reported that thalidomide inhibited angiogene- sis in the rabbit cornea assay8. The next logical step was to test thalidomide in patients with cancer. An open-label (uncontrolled) trial with relapsed and/or refractory MM patients showed that, as anticipated by Folkman’s hypothesis, tha- lidomide was active against advanced tumors, caused a decline in the serum and urine levels of paraprotein (the primary efficacy outcome), a disease remission and apparently an improve- ment of survival9. Since then, evidence from a set of phase II studies confirmed that thalidomide (with dexamethasone and or chemotherapy) significantly improved overall response rates to combined therapies for relapsed and newly diag- nosed patients10,11. A further phase III random- ized clinical trial also showed that, compared to “dexamethasone alone”, “thalidomide plus dexa- methasone” gave rise to superior responses rates in newly diagnosed MM patients12. lenalidomide A phase III placebo-controlled trial revealed that, in patients with relapsed or refractory MM, lenalidomide combined with dexamethasone significantly prolonged “time to progression” (11.3 months versus 4.3 months), and improved overall survival13. In newly diagnosed MM pa- tients ineligible for bone-marrow transplanta- tion, maintenance with lenalidomide after an induction treatment regimen (melphalan + prednisone + lenalidomide) was shown to pro- long “progression-free survival” compared with the induction therapy followed by placebo14. A meta-analysis of seven RCTs evaluating initial or maintenance therapeutic outcomes, such as response rates, “progression-free survival” (PFS), “overall survival” and adverse effects, concluded 3 7 8 7 C iên cia & Saú d e C o letiva, 2 4 (1 0 ):3 7 8 3 -3 7 9 2 , 2 0 1 9 that complete and very good partial response risk ratios, and PFS hazard ratios favored lena- lidomide over placebo15. The occurrence of ad- verse events (neutropenia, deep vein thrombosis, infection and hematologic cancer), however, fa- vored placebo over lenalidomide16. In summary, phase II and III clinical studies showed that both thalidomide- and lenalido- mide-based combination therapies were effective and safe, that is, they substantially improved clin- ical outcomes such as “progression free survival” and “overall survival” in patients with multiple myeloma (MM). Therapeutic regimens based on thalidomide, lenalidomide and, more recently, on the proteasome inhibitor drug bortezomid (it diminishes the activity of cell proteasomes that break down proteins including those that kill ma- lignant cells), revolutionized the therapy of MM, formerly a hematologic cancer of poor progno- sis. MM is a plasma cell proliferative disorder that leads to an accumulation of neoplastic cells (a solid tumor) in the bone marrow. The bene- ficial effects of thalidomide- and lenalidomide- combined therapies in MM patients apparently arise from a dual mechanism of action, while the antiangiogenic activity rapidly reduces MM burden, their long-term immunomodulatory actions seems to maintain tumor suppression17. Effective therapeutic regimens for MM usually also include an antimitotic drug (e.g., melphalan, a potent nitrogen mustard related alkylating agent) and a glucocorticoid (e.g., dexamethasone or prednisone). Comparative effectiveness of thalidomide- versus lenalidomide-based therapies Although presenting similar biological activ- ities, lenalidomide is more potent than thalido- mide, i.e., it achieves responses at lower doses. Higher potency, however, does not imply greater clinical efficacy and two drugs may have different potencies and the same efficacy. To the best of our knowledge, only two ran- domized (phase-III) trials have compared the ef- fectiveness of thalidomide-based versus lenalid- omide-based therapeutic regimens so far (Table 1). Stewart et al.18 conducted a phase III RTC to compare (with a non-inferiority design) a “mel- phalan-prednisone-thalidomide” induction and maintenance with thalidomide (MPT-T) with “melphalan-prednisone-lenalidomide (Revlim- id®)” and maintenance with lenalidomide (MPR-R) in elderly patients with untreated MM. Results showed that there was no difference be- tween MPT-T and MPR-R in response rates, pro- gression free survival (PFS) and overall survival. MPR-R, however, presented a lower occurrence of peripheral neuropathy side effects (Table 1). A similarly designed multicenter open-label RCT by Zweegman et al.19 compared MPT-T and MPR-R regimens in newly diagnosed MM pa- tients who were ineligible for stem cell transplan- tation. Again, this second study showed no supe- riority of MPR-R over MPT-T regarding clinical efficacy (PFS). The trial found, however, an in- creased occurrence of neuropathy in MPT-T, and of hematologic toxicity requiring growth factor support in MPR-R (Table 1). In addition to the foregoing RCTs, three non-interventional studies also addressed com- parative effectiveness of thalidomide- versus lenalidomide-based combination regimens in the therapy of MM (Table 1). A retrospective case-control study (matched-pair analysis ad- justed for age, sex, transplantation status, and dexamethasone dose) by Gay et al.20 compared the efficacy and safety of “thalidomide plus dexamethasone” versus “lenalidomide plus dexa- methasone” as the initial therapy for newly di- agnosed MM. The authors concluded that lena- lidomide-dexamethasone was well tolerated and more effective than thalidomide-dexamethasone. This retrospective study, however, has a number of important methodological limitations, includ- ing the fact that patients treated with thalido- mide-dexamethasone received different doses of thalidomide. It is of note that nearly all authors informed having received honoraria from Cel- gene® Co in their conflict-of-interest disclosure statement. An observational retrospective study conducted in India (analysis of medical record files) compared the efficacy and occurrence of adverse events in 17 patients (newly diagnosed MM) that had received thalidomide-dexameth- asone with 19 patients treated with lenalido- mide-dexamethasone18. The authors found no difference between thalidomide- and lenalido- mide-based therapies with respect to efficacy and safety21. A recent population-based cohort study by Luo et al.22 compared survival and rates of pe- ripheral neuropathy in MM patients (n = 1264) receiving either thalidomide or lenalidomide in routine care in the US. The study found no dif- ference in rates of death (hazard ratio, 95% CI, 1.00, 0.71-1.41) and a lower risk of peripheral neuropathy associated with lenalidomide (0.71, 0.56-0.92). Overall, available comparative effectiveness studies showed no difference in efficacy between lenalidomide- and thalidomide-based therapies 3 7 8 8 P au m ga rt te n F JR T ab le 1 . S tu d ie s o n t h e co m p ar at iv e ef fe ct iv en es s an d s af et y o f th al id o m id e- b as ed v er su s le n al id o m id e- b as ed t h er ap ie s in t h e tr ea tm en t o f m u lt ip le m ye lo m a (M M ). A u th o rs / ye ar s tu d y ty p e s tu d y p o p u la ti o n C o m p ar ed t h er ap ie s C li n ic al o u tc o m e e ffi ca cy e n d p o in ts s id e ef fe ct s St ew ar t et a l. , 2 0 1 5 1 8 P h as e II I R an d o m iz ed C o n tr o ll ed T ri al (n o n -i n fe ri o ri ty d es ig n ) E ld er ly p at ie n ts w it h u n tr ea te d M M M P T -T v er su s M P R -R N o d if fe re n ce i n R R , P F S, a n d O S M P R -R : l o w er i n ci d en ce o f p er ip h er al n eu ro p at h y. Z w ee gm an e t al ., 2 0 1 6 1 9 P h as e II I M u lt ic en te r o p en -l ab el R C T (s tu d y d es ig n s im il ar t o t h at o f St ew ar t et a l.’ s tr ia l) N ew ly -d ia gn o se d M M w h o w er e in el ig ib le t o st em c el l tr an sp la n t M P T -T v er su s M P R -R N o d if fe re n ce i n P F S (p ri m ar y ef fi ca cy e n d p o in t) M P T -T : i n cr ea se d i n ci d en ce o f p er ip h er al n eu ro p at h y M P R -R : i n cr ea se d i n ci d en ce o f h em at o lo gi c to xi ci ty r eq u ir in g gr o w th f ac to r su p p o rt . G ay e t al ., 2 0 1 0 2 0 O b se rv at io n al ( ca se -c o n tr o l d es ig n ed ) re tr o sp ec ti ve s tu d y. M at ch ed - p ai r an al ys is a d ju st ed f o r ag e, s ex , tr an sp la n ta ti o n , D X M d o se + . N ew ly d ia gn o se d M M p at ie n ts ( in it ia l th er ap y) L en al id o m id e + D X M v er su s T h al id o m id e + D X M . L en al id o m id e + D M X : l o n ge r T T P ( m ed ia n 2 7 .4 v er su s 1 7 .2 m o ), P F S (2 6 .7 v er su s 1 7 .1 m o ); O S (n o t re ac h ed v er su s 5 7 .2 m o ). Si m il ar p ro p o rt io n o f p at ie n ts i n t h e 2 g ro u p s ex p er ie n ce d a t le as t o n e gr ad e 3 o r 4 a d ve rs e ev en t (t h al id o m id e ve rs u s le n al id o m id e: 5 4 .6 % v er su s 5 7 .5 % )# S as h id h ar an et a l. 2 0 1 5 2 1 O b se rv at io n al ( an al ys is o f m ed ic al re co rd fi le s) r et ro sp ec ti ve s tu d y. N ew ly d ia gn o se d M M p at ie n ts w h o a tt en d ed m ed ic al c ar e in t er ti ar y h o sp it al s in I n d ia . T h al id o m id e + D X M ( n = 1 7 ) ve rs u s le n al id o m id e+ D X M (n = 1 9 ) P ro p o rt io n o f p at ie n ts s h o w in g m in im al a n d p ar ti al c li n ic al re sp o n se t o t re at m en t (s er u m im m u n o gl o b u li n l ev el s, b o n e m ar ro w b io p sy ) P ro p o rt io n o f ad ve rs e ev en ts d id n o t d if fe r. Y et n o t d if fe ri n g st at is ti ca ll y, 0 4 ( 2 3 .5 % ) p at ie n ts t re at ed w it h t h al id o m id e p re se n te d n eu ro p at h y ag ai n st 0 1 ( 5 .3 % ) th at r ec ei ve d le n al id o m id e. L u o e t al ., 2 0 1 7 2 2 O b se rv at io n al ( p o p u la ti o n -b as ed co h o rt ). P at ie n ts w it h M M re ce iv in g th al id o m id e o r le n al id o m id e in r o u ti n e ca re i n t h e U S. ( N = 1 2 6 4 ) T h al id o m id e- b as ed ve rs u s le n al id o m id e- b as ed t h er ap ie s N o d if fe re n ce i n r at es o f d ea th (H R : 9 5 % C I, 1 .0 0 : 0 .7 1 -1 .4 1 ) L en al id o m id e- b as ed t h er ap ie s: l o w er r is k o f p er ip h er al n eu ro p at h y (H R : 9 5 % C I, 0 .7 1 : 0 .5 6 -0 .9 2 ). m P T -T : I n d u ct io n w it h “ m el p h al an /p re d n is o n e/ th al id o m id e” a n d m ai n te n an ce w it h t h al id o m id e. m P R -R : I n d u ct io n w it h “ m el p h al an /p re d n is o n e/ le n al id o m id e (R ev il im id ® )” a n d m ai n te n an ce w it h l en al id o m id e. D X M : d ex am et h as o n e. + P at ie n ts t re at ed w it h t h al id o m id e an d D X M r ec ei ve d d if fe re n t d o se s o f D X M . A d ve rs e ev en ts w er e gr ad ed a cc o rd in g to t h e U S N at io n al C an ce r In st it u te C o m m o n T er m in o lo gy C ri te ri a. H R : h az ar d r at io . m o : m o n th s. R R : r es p o n se r at es P F S: P ro gr es si o n f re e su rv iv al ; T T P : t im e to p ro gr es si o n ; O S: o ve ra ll s u rv iv al . 3 7 8 9 C iên cia & Saú d e C o letiva, 2 4 (1 0 ):3 7 8 3 -3 7 9 2 , 2 0 1 9 for MM. Nonetheless, studies suggest that lena- lidomide-based regimens are associated with a lower risk of peripheral neuropathy, and a higher risk of hematologic adverse effects (Table 1). Concluding remarks Lenalidomide approval for marketing in Brazil is an unquestionable triumph of a lobbying involv- ing Congress members, patient organizations (most of which supported by the pharmaceutical company) and medical specialty associations. As always, lobbying campaign blurred the scientific evidence behind the arguments for and against an approval for marketing decision. Lenalidomide, thalidomide and proteasome inhibitors (bortezomid) are effective drugs that have revolutionized the treatment of MM. Com- parative effectiveness research failed to demon- strate a greater efficacy of lenalidomide over thalidomide or bortezomid in patients with MM18-21,23. All these drugs can cause potentially severe adverse effects but their toxicity profiles are somewhat different from each other. For in- stance, lenalidomide, compared to thalidomide, apparently causes less peripheral neuropathy and more severe hematologic toxicity. If comparative effectiveness research do not reveal a clinical superiority of lenalidomide over the other drugs, cost-effectiveness seems to be different. Thalidomide-based treatments are cost-effective compared with those based on lenalidomide. This was shown by a study com- paring the cost-effectiveness of initial treatment of MM in the US with “bortezomid (Velcade®) + melphalan + prednisone” (VMP), versus “tha- lidomide + melphalan + prednisone” (MPT), versus “lenalidomide (Revlimid®) + melphalan + prednisone plus lenalidomide maintenance” (MPR-R), and found that VMP cost $119,102, MPT $142,452 and MPR-R $248,35824. Thalid- omide-based therapies, however, are certain- ly much cheaper in Brazil where a state-owned pharmaceutical industry (FUNED-MG) produc- es – at very low manufacturing costs - the thalid- omide used in the country. It was estimated, for instance, that US brand-name thalidomide (Tha- lomid®) costs approximately 122-fold the thalid- omide made by Brazilian FUNED2. Therefore, the eventual substitution of thalidomide-based therapies by those based on lenalidomide is like- ly to raise substantially healthcare costs in the country without a significant (if any) improve- ment of treatment effectiveness. Another major problem with lenalidomide approval in Brazil is the establishment of a reg- ulatory double standard for analogous drugs having in common a high teratogenic risk (Table 2). Owing to risk of harm to the unborn child, thalidomide is regulated by a specific Federal law (Law No.10.651/2003) that prohibits its sale and or dispensing in commercial pharmacies. It also states that thalidomide shall be distributed exclusively to public health units and hospitals. There are a number of additional rules issued by ANVISA that impose strict conditions for prescribing and dispensing thalidomide to ap- proved (and off label) therapeutic indications. The law 10.651/2003, however, makes no pro- vision for lenalidomide and other teratogenic analogues of thalidomide. Unless the Brazilian Congress amends law 10.651/2003, lenalidomide sale, prescribing and dispensing will be regulat- ed exclusively by ANVISA rules, i.e., by agency resolutions that do not have the force of law. Re- cently, ANVISA conducted a public consultation (CP No. 393/2017) on a Regulatory Act on the control of lenalidomide. A key difference regard- ing the current thalidomide control regulation in the country is that, in the case of lenalidomide, it is up to the drug manufacturing company the implementation of a detailed plan on the sales, distribution and dispensing that must comply with a Pregnancy Prevention Plan approved by the agency (Table 2). Finally, there is no reason for a regulatory double standard for lenalidomide and thalido- mide and, therefore, law 10.651/2003 should be amended to include lenalidomide and any other thalidomide analogue. The rules for prescription and dispensing of lenalidomide should be the same prevailing for thalidomide and thus, pro- motion of lenalidomide prescription and adver- tisement by the pharmaceutical company should be forbidden. The use of lenalidomide should be controlled by health authorities and restricted to those patients who cannot otherwise be treated with more cost-effective alternatives (e.g., be- cause of peripheral neuropathy side effects). 3 7 9 0 P au m ga rt te n F JR Table 2. Brazilian asymmetric regulatory standards for thalidomide and its teratogenic analogue lenalidomide. Thalidomide lenalidomide Brand name Generic name Revilimid® Manufacturer State owned (public) industry (FUNED-MG) Pharmaceutical company (Celgene® Co) Potential to cause birth defects (teratogenicity) Proven to humans and non-human primates Proven to non-human primates (likely human teratogen) Regulation Federal Law (10.651/2003) and additional rules issued by ANVISA Regulation to be issued by ANVISA (Public Consultation No. 393/2017) Sales Prohibited No restriction. Costs Low cost medicine (very) High cost medicine Promotion of Prescription & Advertisement Prohibited (nonexistent) Allowed if directed to prescribers (as any other prescription drug)+ Use for off-label therapeutic indications Strictly controlled by ANVISA Uncontrolled by ANVISA Drug distribution and dispensing Exclusively to public health units and hospitals (controlled by health authorities) Distribution and dispensing controlled by the company Authorized prescribers / pharmacists Registered by local health authority Qualified and registered by the company. + According to PC 393/2017 (Art,45), “any” advertisement of lenalidomide is forbidden. However, Art.45 (paragraph) makes an exemption for advertising lenalidomide-based medicines in publications intended to medical or scientific purposes. 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