The FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective

New Drug Approvals

How Drugs are Developed and Approved

The mission of FDA’s Center for Drug Evaluation and Research (CDER) is to ensure that drugs marketed in this country are safe and effective. CDER does not test drugs, although the Center’s Office of Testing and Research does conduct limited research in the areas of drug quality, safety, and effectiveness.

CDER is the largest of FDA’s five centers.   It has responsibility for both prescription and nonprescription or over-the-counter (OTC) drugs. For more information on CDER activities, including performance of drug reviews,  post-marketing risk assessment, and other highlights, please see the CDER Update: Improving Public Health Through Human Drugs The other four FDA centers have responsibility for medical and radiological devices, food, and cosmetics, biologics, and veterinary drugs.

Some companies submit a new drug application (NDA) to introduce a new drug product into the U.S. Market.  It is the responsibility of the company seeking to…

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Drug discovery

New Drug Approvals

In the fields of medicinebiotechnology and pharmacologydrug discovery is the process by which new candidate medications are discovered.

Historically, drugs were discovered through identifying the active ingredient from traditional remedies or by serendipitous discovery. Later chemical libraries of synthetic small moleculesnatural products or extracts were screened in intact cells or whole organisms to identify substances that have a desirable therapeutic effect in a process known as classical pharmacology. Sincesequencing of the human genome which allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to use high throughput screening of large compounds libraries against isolated biological targets which are hypothesized to be disease modifying in a process known as reverse pharmacology.

Hits from these screens are then tested in cells and then in animals for efficacy. Even more recently, scientists have been able to…

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FDA Issues Draft Guidance on NCE Exclusivity Determinations

New Drug Approvals

Feb 25, 2014
FDA has released draft guidance on the agency’s interpretation of the five-year new chemical entity (NCE) exclusivity provisions as they apply to certain fixed-combination drug products (fixed-combinations).  The guidance document states that FDA, historically, has said that a fixed-combination was ineligible for five-year NCE exclusivity if it contained a previously approved active moiety, even if the product also contained a new active moiety (i.e., an active moiety that FDA had not previously approved).

The guidance states that because fixed-combinations have become increasingly prevalent in certain therapeutic areas (e.g., cancer, cardiovascular, and infectious disease) and play an important role in optimizing adherence to dosing regimens, FDA is revising their interpretation of the five-year NCE exclusivity provisions “to further incentivize the development of certain fixed-combination products.” FDA intends to apply the new interpretation prospectively. The guidance, however, does not apply to fixed-combination drug products that were approved prior to…

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FDA publishes new Guidance on Validation of Analytical Methods

New Drug Approvals

The FDA has published a new Guidance on the validation of analytical methods which shall replace the 14 years old existing Guideline on the topic. More details about the contents of this highly topical document can be found here.

A new FDA Guidance for Industry entitled “Analytical Procedures and Methods Validation for Drugs and Biologics” was published a few days ago. This Guideline replaces the Guidance for Industry “Analytical Procedures and Methods Validation” from 2000 (this document has never been finalised and has had a draft status 14 years long) and – when finalised – should also replace the “Guidelines for Submitting Samples and Analytical Data for Methods Validation” which came into force in 1987.

Unlike the previous Guideline from 2000, the new document explicitly mentions biologics in its title. The objective of the Guideline is to inform applicants about what data are…

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Regulatory Considerations for Biosimilars

New Drug Approvals

Biological medicines are already becoming an increasingly important part of health care. With patent expiries on originator biological products, biosimilars are also increasingly become a part of this future. In fact, by 2020 twelve of the top-selling biologicals will have lost patent protection, opening up an estimated US$24 billion in EU sales and US$30 billion in US sales.

Biologicals have potential to reach up to 50% share in global pharmaceutical market in the next few years.

India is one of the leading contributors in the world biosimilar market and is the third-largest in the Asia-Pacific region, after Australia and China. India has demonstrated high acceptance of biosimilars, which is reflected in the 40 biologicals marketed in India, of which 25 are biosimilars The Indian biotechnology industry is also gaining momentum, with revenues of over US$4 billion in 2011, and which are projected to reach up to US$580 million by 2012.

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Americas Health Authorities Meeting

Regulatory Affairs in Latin America

On the 20th and 21st of February of 2014, representatives of the five Latin-American Health Authorities of Regional Reference recognized by the Pan American Health Organization, plus those of the FDA, Health Canada, and El Salvador’s regulatory agency met in Acapulco, Mexico, for a Summit of Health Authorities.

The topics of the agenda were regulation harmonization, reduction of transaction costs, and facilitation of access to drug products and vaccines of high quality and low cost.

Representatives of the American Health Authorities. Photo: COFEPRIS website. Representatives of the American Health Authorities. Photo: COFEPRIS website.

The Health Authorities certified as of Regional Reference currently are those of Mexico (COFEPRIS), Argentina (ANMAT), Colombia (INVIMA), Brazil (ANVISA) and Cuba (CECMED). During the meeting, the representatives of FDA and Health Canada announced their decision to seek the PAHO certification for their own institutions.

The recognition will follow an evaluation of the agencies’ performance of basic functions, recommended by WHO, for ensuring the quality, safety…

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The US FDA has issued full approval for Israeli drugmaker Teva’s Synribo (omacetaxine mepesuccinate)高三尖杉酯碱 for chronic myeloid leukaemia (CML).

New Drug Approvals

Omacetaxine mepesuccinate 高三尖杉酯碱

Alkaloid from Cephalotaxus harringtonia; FDA approved orphan drug status for Ceflatonin in the treatment of chronic myeloid leukemia due to being an inducer of apoptosis in myeloid cells and inhibitor of angiogenesis.
26833-87-4 CAS NO

1-((1S,3aR,14bS)-2-Methoxy-1,5,6,8,9,14b-hexahydro-4H-cyclopenta(a)(1,3)dioxolo(4,5-h)pyrrolo(2,1-b)(3)benzazepin-1-yl) 4-methyl (2R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl)butanedioate

1-((11bS,12S,14aR)-13-methoxy-2,3,5,6,11b,12-hexahydro-1H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]cyclopenta[b]pyrrolo[1,2-a]azepin-12-yl) 4-methyl 2-hydroxy-2-(4-hydroxy-4-methylpentyl)succinate

Also known as:  NSC-141633,

  • BRN 5687925
  • Ceflatonin
  • CGX-635
  • Homoharringtonine
  • Myelostat
  • NSC 141633
  • Omacetaxine mepesuccinate
  • Omapro
  • Synribo
  • UNII-6FG8041S5B
  • 高三尖杉酯碱

CGX-635-14 (formulation), CGX-635, HHT, ZJ-C, Myelostat, Ceflatonin

 USFDA on 26th October 2012  APPROVED

US FDA:    link

Mol. mass545.62 g/mol
Melting Point: 144-146 °C
 FEBRUARY 17, 2014

The US Food and Drug Administration has now issued full approval for Israeli drugmaker Teva’s Synribo (omacetaxine mepesuccinate) for chronic myeloid leukaemia (CML).

Synribo is indicated for adult patients with chronic phase (CP) or accelerated phase (AP) CML with resistance and/or intolerance…

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FDA Guidance on Polymorphic Compounds in Generic Drugs

The guidance issued by the US Food and Drug Administration  advises companies on how to treat polymorphic drug compounds—those that exhibit multiple structural forms—in filing abbreviated new drug applications (ANDAs). The bottom line, according to the guidance, is that generic drug products containing the polymorphs be the “same” as the reference listed drug (RLD) in active ingredients, bioavailability, and bioequivalence.

The guidance pertains to orally available drugs that are either solid- or suspension-dosage products.

Polymorphisms arise when compounds are identical chemically, but not structurally. This can happen when two solids take on different crystalline forms—such as graphite and diamond; when molecules are disordered and fail to produce a repeatable crystal lattice, as is the case for the molecules in glass; or when solvent is trapped inside the crystal structure—as in hydrates, where water molecules are found within crystals.

The guidance notes that different polymorphisms may alter physical properties of compounds and affect their solubility, which in turn can alter their bioavailability or bioequivalence. In addition, polymorphic forms of a compound may alter the way the compound behaves during production, which again, may alter the finished drug’s biological activities.

On this latter point, the guidance specifically states, “Since an ANDA applicant should demonstrate that the generic drug product can be manufactured reliably using a validated process, we recommend that you pay close attention to polymorphism as it relates to pharmaceutical processing.”

The guidance also emphasizes the effect polymorphisms may have on drug stability, which again, may alter the drug’s biological activity.  But the guidance goes on to say that “it is the stability of the drug product and not stability of the drug substance polymorphic form that should be the most relevant measure of drug equality.” Otherwise, a generic drug can be considered the “same” as the active ingredient in an RLD if the generic compound conforms to the standards set out in a United States Pharmacopeia (USP) monograph, if one exists for that particular drug substance.

These standards generally include the chemical name, empirical formula, and molecular structure of the compound. However, the “FDA may prescribe additional standards that are material to the sameness of a drug substance.” But as concerns polymorphisms, the guidance goes on to say “…differences in drug substance polymorphic forms do not render drug substances different active ingredients for the purposes of ANDA approvals….”

Finally, the guidance reminds ANDA applicants that the biological performance characteristics of a drug are also dependent on the drug’s formulation and advises applicants to consider the properties of both the drug substance and formulation excipients, when assessing “sameness.”

A sponsor of an Abbreviated New Drug Application (ANDA) must have information to show that the proposed generic product and the innovator product are both pharmaceutically equivalent and bioequivalent, and therefore, therapeutically equivalent.

Many pharmaceutical solids exist in several crystalline forms and thus exhibit polymorphism. Polymorphism may result in differences in the physico-chemical properties of the active ingredient and variations in these properties may render a generic drug product to be bioinequivalent to the innovator brand. For this reason, in ANDAs, careful attention is paid to the effect of polymorphism in the context of generic drug product equivalency.

This review ..Adv Drug Deliv Rev. 2004 Feb 23;56(3):397-414……discusses the impact of polymorphism on drug product manufacturability, quality, and performance. Conclusions from this analysis demonstrate that pharmaceutical solid polymorphism has no relevance to the determination of drug substance “sameness” in ANDAs.

Three decision trees for solid oral dosage forms or liquid suspensions are provided for evaluating when and how polymorphs of drug substances should be monitored and controlled in ANDA submissions. Case studies from ANDAs are provided which demonstrate the irrelevance of polymorphism to the determination of drug substance “sameness”. These case studies also illustrate the conceptual framework from these decision trees and illustrate how their general principles are sufficient to assure both the quality and the therapeutic equivalence of marketed generic drug products.


ANDAs: Pharmaceutical Solid Polymorphism – Food and Drug   click here


Issues of Polymorphism and Abbreviated New Drug Applications click here


POLYMORPHISM OF DRUGS – Seventh Street Development Group click here

An Overview of Solid Form Screening During Drug  – ICDD..

Although polymorph/salt screening should ideally be performed to select the optimum solid form upon selection of the lead compound prior to animal pharmacokinetic (PK) studies, these screening study can be costly and time consuming. But the consequences of late discovery of a thermodynamic form are grave, so there must be a strategy to minimize the risk without spending a large amount of resources.

We find this right strategy based on early BCS classification of new compounds. We tailor the upfront polymorph/salt studies based on the risk in bioavailability, stability and manufacture-ability. Since regulatory agencies worldwide require the use of the same salt across preclinical and clinical studies, for insoluble or unstable compounds, salt screening is done early to enable further compound development.

Once salt is selected, the polymorph screening of the selected salt if soluble may be done a little later after animal study. However it is paramount to confirm 1) the polymorph in use is stable in the toxicological vehicle, 2) no changes of solid forms during shipping and storage, 3) no significant degradation upon storage.

Should there be polymorphic changes such as formation of a hydrate in the animal vehicle resulting in lowered solubility and precipitation of the hydrate, or formation of a hydrate when exposed to humidity during shipping and storage, early discovery of the stable forms will enable consistent animal exposure and avoid study repeats and delays in timelines.

Therefore, although most companies do not perform comprehensive polymorph screening until late in the development cycle, we recommend identification of a thermodynamic stable form within the confine of not only the API manufacture processes but also in the designated animal and human formulations.

For instance, for a drug product manufactured by direct compression, the solidstate properties of the active ingredient will likely be critical to the manufacture of the drug product, particularly when it constitutes the bulk of the tablet mass.

On the other hand, for a drug product manufactured by wet granulation, the solidstate properties of the active ingredient may no longer be important but the potential for polymorphic conversion is high in the presence of high moisture contents. In the context of the effect of polymorphism on pharmaceutical processing, what is most relevant is the ability to consistently manufacture a drug product that conforms to applicable in-process controls and release specifications.

This upfront work is especially critical to insoluble compounds prone to varied oral bioavailability in animal and human.

Topiroxostat for gout and hyperuricemia

New Drug Approvals




Figure JPOXMLDOC01-appb-C000001




Approved in japan PMDA JUNE 28 2013

Xanthine oxidase inhibitor


Launched – 2013, Fuji YakuhinSanwa, Topiloric  Uriadec

IUPAC Name: 4-(5-pyridin-4-yl-1H-1,2,4-triazol-3-yl)pyridine-2-carbonitrile

CAS Registry Number: 577778-58-6

4 – [5 – (pyridin-4 – yl)-1H-1, 2,4 – triazol-3 – yl] pyridine-2 – carbonitrile (1)



AC1NRB9T, Topiroxostat (JAN/INN),  DB01685, D09786, FYX-051


C13H8N6 MF,248.2482 MW



A xanthine oxidase inhibitor used to treat gout and hyperuricemia.




FYX-051, TOPIROXOSTAT is a xanthine oxidase inhibitor. This agent was approved in Japan by Fuji Yakuhin and Sanwa for the treatment of gout and hyperuricemia in 2013 and launched at the same year. In 2009, the compound was licensed to Sanwa by Fuji Yakuhin in Japan for the codevelopment and commercialization of gout.

The number of patients with hyperuricemia in Japan is reported…

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QTPP. The Quality Target Product Profile


Described in ICH Q8 guide (R2) published in 2009 as “A prospective summary of the quality characteristics of a drug product […]”, the Quality Target Product Profile (QTPP) is based on the approach of Quality by Design (QbD). The QTPP is a product description that summarizes the characteristics expected during the development to respond to the therapeutic drug target.

It is established from the elements relating to the active molecule, its identity, purity or stability, highlighted during the early stages of research and development but also from the scientific data studies of pharmaco-toxicology, pharmacokinetics and clinics. The QTPP concerns not only the active substance itself, based on the activity of the product, but also the dosage form chosen which allows to bring the product to its therapeutic target with the desired concentration.

This document formalizes the state of knowledge of the future stage of drug development.

Summary document should allow the QTPP ultimately justify the choice of the dose, the nature of the packaging, the track and the delivery device. The different characteristics of the product should provide an answer on the fate of the product after its administration to ensure its bioavailability necessary for its effectiveness and safety.

For the active substance, a molecule and the characterization of the impurities is expected. The structure of the drug substance (conformation, molecular weight …), its physicochemical properties (pH, melting point, solubility, polymorphism …) must be entered in the QTPP. The impurities present in the active substance, the potential toxicity of which must be evaluated, need to be studied in order to elucidate their structure and to send the quantification by suitable analytical methods.

Impurities can be obtained from the processing or degradation of the active molecule itself ( product related Impurities ) but also come from components and materials used in the process ( process related Impurities ).Specifications must be specified for each identified and a description of quality control methods used attribute. In view of these different quality attributes, the results of studies of pharmaco-toxicology in vitro and in vivo provide rational needed to provide evidence of their impact on the activity and safety of the product. Functional testing, supporting the mechanism of action of the product, require to be described.

Some characteristics of the finished to meet the required efficiency and safety of the drug product are required in QTPP. The selected dosage form, which may be different during the phases of clinical evaluation of the product and at the time of marketing, must ensure the stability of the molecule and allow its distribution in the body with the desired concentration in order to act on the biological target .

As such, the composition of the final product, unit concentration of active substance and components, as well as its physicochemical characteristics may affect its bioavailability and tolerance (pH, osmolality, disintegration, dissolution …) need to be specified in QTPP. Rational selection of excipients, their function and compatibility will justify both a qualitative and quantitative point of view, their presence in the final dosage form.

Toxicology studies and animal and human pharmacokinetics as well as the results of clinical studies will reinforce these choices. Related to the route of drug administration, specific features can be highlighted. This is the case, for example, injectable products for which sterility and pyrogen are essential requirements to ensure patient safety.

The package is taken into account to ensure product stability and integrity. Interactions container / content supported by studies highlight the presence or absence in the future drug leachables from materials in contact with the product. The identification of these substances, the evaluation of their potential toxicity but their quantification by suitable methods are part of the document. The QTPP should include criteria to justify the integrity of packaging and storage conditions necessary to ensure the quality of the product.

The QTPP is an essential document that enables the formalization and tracing the evolution of the knowledge acquired throughout the lifecycle of the drug. Established during the early stages of development in addition to the Target Product Profile (TPP), it should be updated following the changes in the manufacturing process, a change in the dosage form or in function of the evolution of knowledge Product.

This is a reference element of the expected quality of the product during transfer and scale-up or during comparability studies. The characteristics mentioned in the document must be justified to meet the required efficiency and safety. In this respect, the rational present in QTPP must be clearly expressed and information contained deserve crossed with those described in the literature on products of the same family.

Its establishment and update require the pooling of skills and multidisciplinary knowledge, scientific, medical, technical and regulatory, making it a useful communication tool for the understanding of the product in relation to the claimed therapeutic target.

Risk Assessment of Potentially Genotoxic Impurities within the Framework of Quality by Design



A strategy for the risk assessment of potentially genotoxic impurities is described that utilizes Quality by Design in an effort to furnish greater process and analytical understanding, ultimately leading to a determination of impurity criticality. By identifying the risks and parameters that most influence those risks, an enhancement of both product and process control is attained that mitigates the potential impact of these impurities. This approach calls for the use of toxicological testing where necessary, chemical fate arguments when possible, multivariate analyses to develop design space, and use of spiking data to support specifications. Strong analytical support, especially with the development of low-level detection methods, is critical. We believe that this strategy not only aids in the development of a robust API process but also delivers on the identification and subsequent mitigation of risks to a class of impurities that are of high interest in the field.

Risk Assessment of Potentially Genotoxic Impurities within the Framework of Quality by Design

Adam R. Looker, Michael P. Ryan, Bobbianna J. Neubert-Langille and Redouan Naji
Org. Process Res. Dev., 2010, 14 (4), pp 1032–1036
pp 1032–1036
Publication Date (Web): April 7, 2010 (Communication)
DOI: 10.1021/op900338g

Zanamivir, Relenza…For the prevention and treatment of influenza A and B.

New Drug Approvals



APPROVED 26-7-96……. GSK NDA 021036

A guanido-neuraminic acid that is used to inhibit neuraminidase.

Zanamivir INN /zəˈnæmɨvɪər/ is a neuraminidase inhibitor used in the treatment and prophylaxis of influenza caused by influenza A virus andinfluenza B virus. Zanamivir was the first neuraminidase inhibitor commercially developed. It is currently marketed by GlaxoSmithKline under the trade name Relenza as a powder for oral inhalation.

The drug is approved for use for the prevention and treatment of influenza in those over the age of 7 in the United States, Canada, European Union, and many other countries. It is not recommended for people with respiratory problems and ailments.

United States6294572APPROVED  1994-12-15EXPIRY 2014-12-15
United States5360817                   1993-07-26            2013-07-26
Canada2291994 …

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