关于NDA 505 (b)(2)的理解

This lesson is supported by an educational grant fromDrug Store News is approved by theAccreditation Council for Pharmacy Education(ACPE) as a provider oflogical advances necessary to create bio-pharmaceuticals, these medications car-ry a higher price tag. These medications also target a smaller patient population, such as those with rare cancers or im-munologic disorders. In order to recov-er the cost of creating and marketing these technological miracles, manufac-turers are forced to charge huge prices. Unfortunately, no generic formulations of these medications are available cur-rently, predominantly because of patent coverage. However, the patents on nu-merous biotech agents have expired or will expire soon, including human in-sulin and human growth hormones. THE HATCH-WAXMAN ACTThe Hatch-Waxman Act, formally known as the Drug Price Competition and Patent Term Restoration Act of 1984, was an attempt to balance the need for innovation with the desire for lower-cost alternatives within a reasonablelength of time. The two categories of ap-plications for Food and Drug Adminis-tration (FDA) medication approval with which health care professionals are most familiar are NDAs, used for innovator drugs, and ANDAs, used for generic products. The NDA process for innova-tor products is described in section 505(b)(1) of Federal Food, Drug and Cosmetic Act. The approval process for these products requires full reports of investigations of safety and effective-ness conducted by or for the applicant or for which the applicant has the right of reference for the information submitted. These medications are innovator prod-ucts protected by patent laws.The right of reference means the authority to rely upon an investigation for the purpose of obtaining approval of an application, including the abili-ty to make available the underlying raw data from the investigation for FDA audit. Data used in the 505(b)(1) process typically are based on research for which the applicant has the right of reference because the applicant has conducted the research or paid to have it done.The ANDA process for generic prod-ucts is described in section 505(j). In the ANDA process, the generic manufac-turer only needs to complete studies that demonstrate the generic product to be bioequivalent to the innovator product.All drug products do not fall neat-ly into one of these two categories. For example, a product that has the same active ingredient as a product ap-proved through the 505(b)(1) process, but has a different formulation, cannot be considered for approval as a gener-ic product. Yet, if treated strictly as a “new” drug, it would require all the clinical testing for safety and efficacy that is required of innovator drugs. Keeping in mind that part of the intent of the Hatch-Waxman Act was to in-crease efficiencies in the drug approval process and to avoid unnecessary de-lay and expense in bringing a drug product to market, it is not surprising that the FDA created some special pro-visions for the approval of such prod-ucts. These provisions are embodiedin section 505(b)(2) of the act. Funda-mentally, they enable a drug manu-facturer to submit a drug for approvalbased on existing data about the drugor a similar drug, thus avoiding theneed to conduct research that wouldduplicate that data. Instead, what maybe submitted are full reports of inves-tigations of safety and effectivenesswhere at least some portion of the in-formation submitted for approvalcomes from studies not conducted byor for the applicant and for which theapplicant has not obtained the right ofreference for the information undersection 505(b)(2) of the Act. The typesof information an applicant can rely oninclude published literature describ-ing study results and the FDA’s find-ings of safety and effectiveness from apreviously approved medication.Products approved through the505(b)(2) process are considered to bepharmaceutical alternatives to an ap-proved medication.APPROVAL UNDER SECTION 505(B)(1)When a pharmaceutical manufacturerdevelops a new medication, the FDArequires extensive testing to provethe safety and efficacy of the productbefore it can be marketed. The approvalprocess is regulated by numerous lawsoutlining strict requirements. The firstattempt to regulate medications manu-factured in the United States was theFederal Food and Drug Act of 1906, re-quiring that medications marketed ininterstate commerce meet minimal stan-dards of strength, purity and quality.This law made no attempts to regulatetherapeutic claims. This act soon wasfollowed by the Sherley Amendment in1912, allowing for the regulation offraudulent claims of therapeutic effectsthrough the regulation of labeling. TheFDA finally gained the authority toevaluate and approve medicationsbased on their safety profile until theFood and Drug Act was updated by theFederal Food, Drug and Cosmetic Actof 1938. It was not until 1962 whenthe Kefauver-Harris Amendment waspassed that the FDA gained authorityto require proof of efficacy in order togain FDA approval.In order to prove safety and efficacy,pharmaceutical manufacturers are re-quired to complete extensive clinicaltrials, consisting of three phases. PhaseI clinical trials are intended to assess thepharmacologic and pharmacokinetic ac-tivity of the drug in humans. In thesestudies, the medication is administeredto a small number of healthy volunteers.Phase II clinical studies are intended toobtain preliminary data related to theeffectiveness of the medication in pa-tients suffering from the disease orcondition being evaluated. Along withassessing effectiveness, information isgathered pertaining to side effects andrisks associated with the medication. Iffavorable results are obtained in PhaseII trials, Phase III trials are performed.The size of trial is determined by theprevalence of the condition being treat-ed, the power necessary to discern clin-ical outcomes and the medication’ssafety profile. Typically, several hun-dred to several thousand participantsare required in order to yield sufficientinformation pertaining to safety, effica-cy and the overall risk-benefit ratio foruse of this product in humans. When allthree phases are complete, the manu-facturer submits an NDA containingresults from these studies to the FDA.FDA scientists review the NDA to as-sess whether the trials demonstrate theproduct’s benefit, compared with itsrisks. During the evaluation process, theFDA reviews the study outcomes, chem-istry, manufacturing, controls, labeling,bioavailability, stability and compliancewith good manufacturing standards.By the time an NDA is approved, themanufacturer has invested numerousyears and many millions of dollars fordevelopment, clinical trials and regula-tory approval. As compensation, theFDA grants the company the exclusiveright to manufacture the product underpatent protection. Prior to 1995, patentprotection typically lasted 17 years fromthe date the patent was issued. Follow-ing the Uruguay Rounds AgreementsAct (Public Law 103-465) in 1995, man-ufacturers are granted patent protectionfor 20 years from the date of the firstfiling of the patent application. Becauseproducts usually are patented beforethey reach clinical trials, many years ofpatent life have passed before the NDAis approved. The Patent Term Restora-tion, another component of the Hatch-Waxman Act, does allow the manufac-turer to reclaim some of the time lostduring development and approval. TheFDA can extend the patent by the lengthof time required for the regulatoryprocess plus one-half of the time re-quired for the clinical trials, the total ofwhich is not to exceed five years. Oncethe patent has expired, other manufac-turers can petition the FDA for approvalof a generic version.GENERIC APPROVAL PROCESSSECTION 505(J)Before 1984, generics manufacturers hadto complete the same time-intensive andcostly clinical trials that the innovatingmanufacturer submitted with its NDA.This act created an abbreviated proc-ess for generic product approval, theANDA. Before submitting an ANDA,the generic manufacturer only needs tocomplete studies that demonstrated thegeneric product to be bioequivalent tothe innovator product. No longer re-quired to repeat clinical trials, genericsmanufacturers are able to obtain ap-proval in less time and with less expen-diture of resources. This enables themto offer their product at a lower price.In order to manufacture a genericproduct, the FDA mandates that themanufacturer prove its medication:•contains the same active ingredient.•is the same strength, in the samedosage form and is administeredvia the same route.•has the same indications and dosing.•is bioequivalent.•meets the same batch-to-batchrequirements for strength, purityUnderstanding the 505(b)(2) approval processand quality.•is manufactured using good manu-facturing practice regulations simi-lar to those of the brand product.Bioequivalent medications show no significant difference in the rate and extent to which the active ingredient becomes available at the site of action. This is assessed by looking for differ-ences in the plasma concentration-time profile. The first component is the peak concentration of the drug in the blood, known as C max. The second component is the time required to reach the peak concentration after the medication is ad-ministered, referred to as t max. The final component is the area under the curve (AUC), representing the total area un-der the concentration-time curve. The C max, t max and AUC of the generic product cannot be statistically different from those of the innovator product. The results of the concentration-time profile must fall within a 90 percent confidence interval for the ratio of the mean re-sponse and fall within the limits of 80 percent to 125 percent, using log trans-formed data.Based on FDA-established bioequiv-alence of products, substitution of one product for another can be recom-mended without any adjustment in dose or additional therapeutic monitoring. To identify bioequivalent medications, the pharmacist can refer to the “Ap-proved Drug Products with Therapeutic Equivalence Evaluations,” commonly referred to as the “Orange Book.” The Orange Book is so named for the color of the book’s cover and also is available on the FDA’s Web site.UTILIZING THE ORANGE BOOKFOR SUBSTITUTIONSWhen considering medication for sub-stitution, the pharmacist should beaware of the coding system the FDAuses in the Orange Book (Table 3). TheFDA assigns each multisource producta two-letter code, providing informa-tion about equivalency to a referencelisted drug.The first letter, representing theequivalency of the product, is eitheran “A” or “B.” The FDA considers med-ications rated “A” to be therapeuticallyequivalent to its pharmaceuticallyequivalent products. To be consideredtherapeutically equivalent, all actual orpotential bioequivalence problems mustbe resolved with adequate in vivo or invitro bioequivalence evidence.The FDA does not consider medica-tions rated “B” as therapeutically equiv-alent to other pharmaceutically equiva-lent products. “B”-rated products fallinto three main categories:1) products containing an active in-gredient or in a dosage form with doc-umented or potential bioequivalenceproblems for which adequate data tosupport bioequivalence has not beensubmitted to the FDA, or2) products with inadequate qualitystandards or insufficient basis to deter-mine therapeutic equivalence, or3) products currently undergoingFDA review.The second letter represents anyadditional information the FDA dis-covered during its evaluation. Theseletters are usually “A,” “B,” “N,” “O,”“P” or “T.” The information providedby this letter often is related to thedosage form of the product. AB-ratedproducts are those for which “actual orpotential bioequivalence problemshave been resolved with adequate invivo and/or in vitro evidence support-ing bioequivalence.”12Although all“A”-rated products are consideredbioequivalent, this bioequivalence hasbeen proven scientifically with AB-rat-ed products. AA, AN, AO, AP, AT-rat-ed products do not have any suspectedor proven bioequivalence problems,but the necessary bioequivalence in-formation is presumed. Despite thislack of information, these products arestill considered bioequivalent.In the late 1970s, states beganencouraging substitution with genericproducts. As of 2004, 11 states mandat-ed generic substitution when anappropriate generic is available, whilethe other 39 permit the pharmacist tosubstitute equivalent products. States’regulations vary on which medicationsare substitutable. Many states allow sub-stitution only with AB-rated medica-tions. Some states, such as Massachu-setts, utilize positive formularies for sub-stitution. Within positive formularies,only medications listed in the formula-ry are eligible for substitution.APPROVAL UNDER SECTION 505(B)(2)Section 505(b)(2) of the Hatch-WaxmanAct is intended to promote innovation,while saving time and resources andavoiding unnecessary duplicate hu-man testing. Medications approved un-der this section are not completely newproducts, yet they do not qualify forapproval as generics. These medica-tions contain some differences from areference listed drug, while offering atherapeutic alternative. NDA approvalunder section 505(b)(2) is not intend-ed to infringe on patent and exclusiv-ity protections of other medications.Since 1987, the FDA has approvedmore than 100 applications submittedunder section 505(b)(2).In the 505(b)(2) application, the ap-plicant relies on information from stud-ies it did not conduct and does not havethe right of reference.Although the manufacturer may nothave performed the studies, it must sub-mit clinical and non-clinical data todemonstrate the medication is safe andeffective. It also must be able to providedata and information, including bio-availability or comparative bioavail-ability studies, to establish sufficientlythe appropriateness of relying on mate-rial without the right of reference.Not all applications are eligible forsubmission under section 505(b)(2). A505(b)(2) application is not appropriatefor medications eligible for ANDA ap-proval as a generic or medications inwhich the only difference from the ap-proved product is the extent or rate inwhich the active ingredient is absorbedor otherwise made available to the siteof action. Submissions that do qualifyfor 505(b)(2) approval include productsthat have the following characteristics:•dosage form change,such as a solidoral preparation to a transdermalmatch, that relies to some extenton FDA safety and effectivenessfindings.•change in strength.•change in the route of administration,such as a change from subcutane-ous to intravenous route.•substitution of an activ e ingredientin a combination product for an-other active ingredient (both ofwhich previously have been ap-proved individually).•formulation change,including pro-posed drug products that containa different quality or quantity ofan excipient.•dosing regimen change.•different activ e ingredient,such as adifferent salt, ester, complex, chelateor enantiomer.•new molecular entity if the entity wasstudied by parties other than the ap-plicant, particularly if the proposedmedication is the prodrug or metabo-lite of an approved medication.•new combination product in whichthe active ingredients previouslyhave been approved individually.•new indications.•change a prescription to an ov er-the-counter indication.•naturally derived or recombinant activeingredient for which clinical investi-gations are necessary to show theactive ingredient is the same as anapproved medication.Important medication approvalshave occurred through this approvalpathway. In particular, section 505(b)(2) is crucial in areas of drug development where limited or uncertain markets war-rant maximum utilization of available knowledge. For example, pharmaceuti-cal manufacturers often formulate med-ications in dosage forms and regimens intended for adults. After approval of the adult formulation, manufacturers may seek approval for a different for-mulation for children. Along with drain-ing resources and delaying approval, repeating extensive clinical trials to demonstrate effectiveness could put study subjects at unnecessary risk.Even the United States Army has utilized section 505(b)(2) to expedite ap-proval of agents necessary to protect military personnel during times of war. In this era of concern about biological weapons, military personnel require pre-treatment against nerve agents. In the event of exposure, military person-nel require easy and rapid administra-tion of treatments. In order to obtainapproval for use of pyridostigmine bro-mide as pretreatment to increase sur-vival after exposure to the nerve agentSoman, the Army was required to sub-mit data demonstrating safety and effi-cacy. The exposure of subjects to Somanin order to prove safety and efficacywould have been unethical. Therefore,the Army utilized efficacy data from an-imal studies and safety informationfrom pyridostigmine bromide use forthe treatment of myasthenia gravis. Toprovide treatment in the event of nerveagent exposure, military personnelcarry atropine and pralidoxime autoin-jectors. For quicker administration ofthese medications, the Army submittedan NDA to combine these products inone autoinjector.LEGAL ISSUESApproving medications under section505(b)(2) has been challenged by someparties. The application process allowsapplicants to utilize published litera-ture and the FDA’s prior findings ofsafety and effectiveness of an approvedmedication. Some innovator manufac-turers have filed citizens’ petitionsagainst the use of FDA’s prior findings.These FDA findings are often based onfindings from studies submitted as partof an approved NDA. While publishedliterature is available in the public do-main, data from NDA submissions re-mains proprietary. Although the statu-tory language clearly allows for fullNDA applications that rely on data towhich the applicant does not haveright of reference, language does notclearly specify if that information canextend past published literature. Somepharmaceutical manufacturers arguethe intent of section 505(b)(2) was toallow referencing only portions of anNDA application available in the pub-lished literature, not proprietary por-tions of data. The FDA has upheld itsposition that section 505(b)(2) permitsreliance on previous FDA findings ofsafety and efficacy.Some innovator manufacturers alsocontend that 505(b)(2) approvals infringeon their patents, while the FDA contendsthat 505(b)(2) medications are designedaround the patent without infringingupon it. Pfizer and Dr. Reddy’s Labora-tories (DRL) waged a highly publicizedlegal battle over amlodipine patents. In1986, Pfizer was granted a patent on theamlodipine molecule. The followingyear, Pfizer filed a subsequent patent ap-plication specifically for the amlodipinebesylate salt, later marketed as Norvasc,®due to superior blood pressure-lower-ing activity than amlodipine maleate. Asthe patent neared expiration, Pfizer filedfor a Patent Term Extension in order torecoup some of the patent life lost dur-ing the approval process. After review-ing Pfizer’s patents, lawyers for DRLconcluded that the Patent Term Exten-sion only covered the besylate salt, ratherthan the amlodipine molecule. DRL sub-mitted an NDA under section 505(b)(2)for the besylate form. In 2002, the FDAgranted approval for amlodipine besy-late (AmVaz®). Meanwhile, Pfizer suedDRL for patent infringement, arguingthat the patent extension covered the am-lodipine molecule. In this case, the U.S.Appeals Court sided with Pfizer’s inter-pretation of its patent.Innovator manufacturers that do notpatent an entire molecule, rather opting topatent only the salt, isomer or activemetabolite that will be FDA approved,often have found that another manufac-turer is waiting to produce other formu-lations. While traditional albuterol prod-ucts contained a mixture of two enan-tiomers, Xopenex®(levalbuterol) containsonly the isomer that exhibits fewer ad-verse effects. Although albuterol is off-patent and available from numerous man-ufacturers, Xopenex®maintains patentprotection and market exclusivity, cost-ing more than twice as much. Sepracoralso co-markets fexofenadine (Allegra®)and desloratadine (Clarinex®), based onprevious patents for terfenadine(Seldane®) and loratadine (Claritin®).Even some generic manufacturershave challenged 505(b)(2) approvals. In2000, Synthon filed a 505(b)(2) applica-tion for paroxetine mesylate tablets (Pex-eva®). The application proved safety andefficacy from published literature, clin-ical trials Synthon performed and pre-vious FDA findings of safety and effi-cacy of a related chemical compound,paroxetine hydrochloride hemihydrate(Paxil®). The FDA approved Pexeva®in 2003. Pexeva®was not AB-ratedto Paxil,®but was a less expensivepharmaceutical alternative offeringequivalent dosing regimens. Within aCASE STUDYUnderstanding the 505(b)(2) approval processmonth after approval of Pexeva,®the FDA approved Torpharm’s generic ver-sion of paroxetine hydrochloride tablets, providing the product with an AB rating to Paxil.®Torpharm submitted a citizens petition to the FDA on the grounds that Pexeva®infringed on its 180-day mar-keting exclusivity as the first generic equivalent to Paxil.®According to the FDA, disallowing 505(b)(2) submissions in their current state would divert industry resources, increase drug costs, strain FDA review resources and slow the approval process without providing an improved health benefit. In addition, the need to dupli-cate trials utilized in previous NDAs has the potential to raise ethical questions pertaining to unjustified testing of ani-mals and humans.WILL 505(B)(2) PROVIDE A BIOGENERIC APPROVAL PATHWAY?Most biotech medications are regulated by laws different from those controlling traditional medications. Because of the complex cellular processing necessary to manufacture biopharmaceuticals, in-novator biopharmaceuticals undergo a different approval process, known as biologics licensing applications.Some concern exists pertaining to the difficulty of replicating all aspects of these molecules, leading to questions about approving biogenerics through the standard ANDA process. Being as the Hatch-Waxman Act was instituted prior to the development of most biopharma-ceutical products, it does not specifical-ly address the approval process for bio-generics. A few simpler biologic med-ications, including recombinant insulin and human growth hormone, do fall un-der the jurisdiction of Hatch-Waxman because the innovator was approved under section 505(b)(1), rather than a biologics licensing application. As of yet, no regulations and guidelines are available in the United States to address approval of biogenerics.The European Medicine Evaluation Agency (EMEA) has issued guidelines concerning biogenerics. The EMEA Committee for Proprietary of Medicinal Product’s guidelines, entitled “Guide-line on comparability of medicinal prod-ucts containing biotechnology-derived proteins as active substance: quality issues,” are primarily devoted to com-parability issues related to a manufac-turer’s alteration in its own production process, but briefly addresses produc-tion of multisource products from oth-er manufacturers. The EMEA recog-nized that generic manufacturers may not have complete access to the innova-tor company’s production information, making them unable to compare all aspects of the products. The guideline recognized that simple biochemical characteristics would be insufficient to establish equivalency, but do not clearly define manufacturing practices and sub-mission requirements for such products.In the United States, one potential but not universally supported approach for dealing with biogenerics is approval under section 505(b)(2). After Sandoz submitted a 505(b)(2) application for Omnitrope®(somatropin [rDNA origin]for injection) to the FDA, citizens’ peti-tions were submitted to the FDA on behalf of Pfizer, the patent holder for Genotropin,®a somatropin product. Ac-cording to the petition, Pfizer requested the FDA deny Sandoz’s application on the grounds that the company deemed it “scientifically and legally improper for the FDA to rely on, reference or other-wise use the clinical and manufacturing information that establishes the safety and effectiveness of Genotropin®… to approve Omnitrop.®” The petition states that the “data submitted to support ap-proval of Omnitrope ‘do not adequately address … the specific product differ-ences between Genotropin®and Omni-trop.®’” Pfizer’s petition was based on Sandoz’s use of FDA’s finding of safety and effectiveness for Genotropin,®which is approved for the same indications as those sought by Sandoz, in conjunction with studies Sandoz performed.Despite Pfizer’s petition, the FDA approved Omnitrope®under section 505(b)(2) in May 2006, following simi-lar approvals by the European Com-mission and Australia. The FDA con-sidered Omnitrope®different from more complex or less well-understood biotech products, being as the FDA has ap-proved eight different recombinant human growth hormone product lines for various indications. Although San-doz was able to demonstrate the pro-teins in Genotropin®and Omnitrope®are highly similar, it did not need to prove they are the same. Sandoz was re-quired only to prove they were similar enough that utilizing FDA findings on safety and efficacy for Genotropin®is appropriate. Submission of an NDA un-der section 505(b)(2) does not intend to prove “sameness.” Being as Sandoz was not seeking an “A” therapeutic rating for Omnitrope,®it will be designated with a “BX” rating in the Orange Book, therefore, making Genotropin®and Omnitrope®not bioequivalent.HOW SHOULD PHARMACISTS DEAL WITH 505(B)(2) MEDICATIONS?Most pharmacists are aware, at least to some extent, of the approval process in-volving traditional NDAs and ANDAs. Pharmacists also must be aware of the 505(b)(2) process in order to make appropriate decisions pertaining to product selection.Section 505(b)(2) allows the FDA to determine what studies are necessary to support approval of a medication, re-ducing the unneeded studies. Therefore, manufacturers of these medications spend less time and money doing re-search and development. These savings are typically passed on to the consumer through lower pricing. For example, the average wholesale price (AWP) for 30 tablets of Paxil®30 mg (paroxetine hydrochloride) is $20 higher than an equivalent amount of Pexeva®(paroxe-tine mesylate), which was approved under section 505(b)(2). The AWP for Pexeva®is similar to that of generic paroxetine hydrochloride products.Although these medications often are less expensive, the pharmacist must remember that these medications are not bioequivalent to a reference-listed。