Tag Archives: Drug Approvals

2015 Report: Progression of Modern Therapeutics

The 2015 Report of Progression of Modern Therapeutics provides graphs of new drug approvals for 40 therapeutic classes from 40 therapeutic categories. These include the 25 therapeutic classes that were in the 2014 Report, any updates on these, and 15 new ones, including irritable bowel syndrome, HIV-1/AIDS, hepatitis C, malaria, melanoma, pediatric acute lymphoblastic leukemia. Click here for the 2015 Report on this website.


As with most projects there are sometimes unexpected issues that come up from time to time, and this project is no different. We will comment on three such issues at this time:

Missing approved new drugs. Since the approach used for what new drug approvals to include involves a therapeutic class centered approach rather than an NME centered approach, it is possible there may be missing drug approvals, since these may involve secondary indications of NME’s or subsequent approvals of the same compound, and would thus not be included in FDA’s annual NME listings. Any such omissions will be corrected as appropriate.

Missing approval dates. For several older drugs, the exact initial approval date may not be listed in the Drugs@FDA database, or other readily available databases. In such cases, a footnote is added to that effect on the graphs for individual therapeutic classes, e.g., pediatric acute lymphoblastic leukemia and migraine; other examples would include tuberculosis.

Off-label use. For some diseases there is considerable off-label use, and a number of drug information websites may include such use, without necessarily distinguishing between FDA approved drugs and off-label use, e.g., migraine. Such examples of clinical use are typically not included on the graphs.

Random Observations and Comparisons

A perusal of this 2015 Report suggests a few lessons learned, including the following random observations and comparisons:

  • Note significant recent advances in new drug approvals for hepatitis C, melanoma, cystic fibrosis, idiopathic pulmonary fibrosis, and irritable bowel syndrome, to name just a few.
  • Note recent introductions of new pharmacologic classes or mechanisms of action for type-2 diabetes, dyslipidemia, multiple sclerosis, pulmonary arterial hypertension, and rheumatoid arthritis, to name just a few.
  • Note no new introductions of new pharmacologic classes for depression (MAO inhibitors, tricyclics, SSRI’s/SNRI’s) and schizophrenia (typical and atypical antipsychotics) since the late 1980’s.
  • Contrast melanoma with 8 new drug approvals since 2010 with childhood acute lymphocytic leukemia with most drugs from the 1950’s, 1960’s and 1970’s.
  • Contrast plaque psoriasis with 7 new drug approvals with systemic lupus erythematous with 1 new drug approval since 2000.
  • What do thrombolysis and acid reflux/gastric ulcer have in common? No new drug approvals since 2000/2001.

The two prior annual update reports (2013 Report and 2014 Report) contained different summary graphics, which are not included in the 2015 Report; these will be addressed in future posts.

ADHD Therapeutics: Slow and Limited Progress


The CNS stimulants amphetamine and methylphenidate were first synthesized in 1887 in Germany and 1944 in Switzerland, respectively, and approved for use in ADHD (Attention Deficit Hyperactivity Disorder) in 1960 and 1955. It is quite amazing that these molecules – and their pharmacologic classes – still serve as the mainstay of ADHD therapy. Although their duration of action is relatively short, development of various modified release formulations has resulted in improved concentration vs. time profiles of these drugs. Other developments have involved the introduction of the dextro enantiomers of these compounds, and more recently, the introduction of a prodrug of the dextro enantiomer of amphetamine.

Drug Approvals

There have been a total of 7 new molecule approvals for this therapeutic class, in 5 pharmacologic classes. The mainstay of therapy, the CNS stimulants amphetamine or methylphenidate, are both racemates, with the dextro enantiomers being the more active enantiomers. The original approvals of amphetamine (Adderall, 1960) and methylphenidate (Ritalin, 1955) involved the racemates. Subsequently, there have been numerous introductions of different formulations of both molecular entities, including modified release formulations of the racemates, the dextro enantiomers of both drugs, and a prodrug of the dextro amphetamine. In keeping with our convention of focusing on new molecules and not listing new formulations or new routes of administration of previously approved compounds, only the original approvals of new molecules are counted. Similarly, prodrugs of previously approved small molecules are not counted, since the active molecular moiety is still the same. However, the first approvals of the dextro enantiomers of both amphetamine and methylphenidate and of the prodrug of the dextro amphetamine are shown for reference on the accompanying chart (click for a larger chart). Also, in keeping with our convention, included are newly approved drugs for this indication, although they may have been previously approved for another indication, i.e., the two alpha-2 adrenergic receptor agonists. The new molecule approvals are listed below:

ADHD Therapeutics

  • Amphetamine (CNS Stimulant): 2 new molecules; Desoxyn (methamphetamine, 1943) and Adderall (mixed amphetamine, 1960). The first dextro amphetamine, Dexedrine (dextroamphetamine, 1976) and the first prodrug of dextro amphetamine, a lysine adduct, Vyvanse (lisdextroamphetamine, 2007), are also shown on the graph for reference.
  • Methylphenidate (CNS Stimulant): 1 new molecule; Ritalin (methylphenidate, 1955). The first dextro enantiomer, Focalin (dextromethylphenidate, 2001) is also shown on the graph for reference.
  • Oxazolidine: 1 new molecule; Cylert (pemoline, 1975); withdrawn due to hepatotoxicity.
  • Selective Norepinephrine Reuptake Inhibitor: 1 new molecule; Strattera (atomoxetine, 2002).
  • Alpha-2 Adrenergic Receptor Agonist: 2 new molecules; Intuniv (guanfacine, 2009) and Kapvay (clonidine, 2009).


It is noteworthy that there have been a total of approximately three times as many introductions in this therapeutic class as there have been new molecule approvals. This is principally due to the approvals of numerous new formulations of both amphetamine and methylphenidate, and their dextro enantiomers, to improve their concentration vs. time profiles. A few specific comments follow:

  • As mentioned above only new molecule approvals are counted. Other approvals are not listed, except for reference. For descriptions of the characteristics of the different new formulations of amphetamine and methylphenidate, and their dextro enantiomers, please refer to a textbook chapter (1). It’s noteworthy in this context that few, in any, therapeutic classes have as many approved new formulations of more than half a century old molecules.
  • It is remarkable that after the initial approvals of the CNS stimulants amphetamine and methylphenidate for ADHD in 1960 and 1955, respectively, that these two compounds still represent the mainstay of therapy, and that there have not been introductions of new active molecules in these pharmacologic classes.
  • Note that the two centrally-acting alpha-2 adrenergic receptor agonists, Intuniv (guanfacine, 2009) and Kapvay (clonidine, 2009), were previously approved for use in Hypertension in the late 1980’s and early 1970’s, as Tenex and Catapres, respectively.


Two old CNS stimulants, amphetamine and methylphenidate, still continue as the active ingredients of the mainstay of ADHD therapy. This suggests there is a need for a renewed research focus on the etiology and pathophysiology of this disease, including genomics, with the goal of identifying improved therapeutic options. Over one year ago, on this website (2), the slow progress in two other psychopharmacologic therapeutics classes, Schizophrenia and Depression, was discussed, although in contrast to ADHD, there has been a number of new molecule approvals for these indications, but these have been confined to a few pharmacologic classes, half of which have their origins in the late 1950’s. Again, these observations strongly suggest a need for more basic research to identify new therapeutic options in the psychopharmacologic therapeutics category.


  1. Mrazek DA, Schak KM: Attention-Deficit/Hyperactivity Disorder, in: Waldman SA, Terzic A, Pharmacology and Therapeutics, Saunders Elsevier, Philadelphia, 2009, pp.759-768
  2. TRI-institute.org: Slow Progress in Psychopharmacologic Therapeutics, Sep 2014, https://tri-institute.org/?p=184.

Refer to page 22 of Progression of Modern Therapeutics (2014 Report) available under Reports on this website; this report also includes the methodology used.


Progression of Modern Therapeutics for Rheumatoid Arthritis


Since 1985, a total of 13 drugs have been approved for rheumatoid arthritis, in 8 different pharmacologic classes. The 1998 approval of Enbrel (etanercept), the first of 5 TNF inhibitor, ushered in the biologic DMARDs (disease-modifying antirheumatic drugs), representing the most significant progress in this therapeutic class; in fact, a total of 9 biologic DMARDs have been approved, the last, Actemra (tocilizumab), in 2010. Five small-molecule DMARDs had been approved between 1950 and 1970. In addition to the DMARDs for rheumatoid arthritis, NSAIDs (nonsteroidal anti-inflammatory drugs) and corticosteroids are sometimes used (not covered here).

Drug Approvals (1)

Excluding the 5 older, small-molecule DMARDs for rheumatoid arthritis, Azulfidine (sulfasalazine, 1950), Methotrexate (methotrexate, 1953), Plaquenil (hydroxychloroquine, 1955), Imuran (azathioprine, 1968), and Cuprimine (penicillamine, 1970), the 13 new drugs approved for rheumatoid arthritis, sorted by the 8 pharmacologic classes, are shown in the accompanying chart (click for a larger chart), and summarized below:

accompanying chart

  • Gold Preparation: 1 new drug; Ridaura (auranofin); in 1985.
  • T-cell Activation Inhibitor: 1 new drug; Neoral (cyclosporine); in 1995.
  • TNF Inhibitors: 5 new drugs; Enbrel (etanercept), Remicade (infliximab), Humira (adalimumab), Cimzia (certolizumab), and Simponi (golimumab); over 10 years and 6 months; between 1998 and 2009.
  • Anti-metabolite: 1 new drug; Arava (leflunomide); in 1998.
  • IL-1/IL-6 Receptor Antagonists: 2 new drugs; Kineret (anakinra) and Actemra (tocilizumab); over 8 years and 2 months; between 2001 and 2010.
  • T-cell Activation Inhibitor: 1 new drug; Orencia (abatacept); in 2005.
  • Anti-CD20/B Cell Depletor: 1 new drug; Rituxan (rituximab); in 2006.
  • JAK Inhibitor: 1 new drug; Xeljanz (tofacitinib) in 2012.


Over the past more than half a century, there has been development, albeit discontinuous, in new drug introductions for rheumatoid arthritis, characterized by two periods. First, the period between 1950 and 1970, when 5 new small-molecule DMARDs were introduced, and second, the period from the late 1990’s to the present, when 12 biologic and small-molecule DMARDs have been introduced.

  • The single most significant advance in the treatment of rheumatoid arthritis involves the introduction of the TNF inhibitors, a total of 5 new drugs.
  • The time from the discovery of TNF (in the 1960s) and from the determination of its structure (in the mid 1980s) until the approval of the first TNF inhibitor, Enbrel, was over three decades and over one decade, respectively.
  • The regulatory requirements for approval of agents for rheumatoid arthritis involve appropriate responses based on the American College of Rheumatology’s treatment assessment criteria ACR(20), ACR(50) and ACR(70), representing >20%, >50%, and >70% improvement, respectively.
  • Recently approved DMARDs have had patient responder rates in the approx. 40-60% range; responder rate typically defined as the proportion of subjects achieving a ACR(20) response at 3 months.
  • Based on a recently proposed systems therapeutic category classification (2), it would appear the majority of the modern therapeutics for rheumatoid arthritis are in Category II, i.e., the pivotal interaction between pharmacologic processes and pathophysiologic processes involves a fundamental biochemical mechanism, related to the disease evolution, although not necessarily an etiologic pathway.
  • In spite of significant developments over the past two decades, there clearly is room for considerable improvements in the efficacy characteristics of therapeutics for rheumatoid arthritis.


  1. Drugs@FDA: Medical Review of Xeljanz, Tables 2 and 3 in Clinical Review, accessed October 2015. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
  2. TRI-institute: Systems Therapeutics: A Diagram and Four Categories. April 2015. https://tri-institute.org, April 2015 post.

Refer to page 26 of Progression of Modern Therapeutics (2014 Report) available under Reports on this website; this report also includes the methodology used. Note the present graph and text have been modified based on information presented in reference 1.

Alzheimer’s Disease: Many Years To Go


On 3 November 1906, Dr. Alois Alzheimer, a German psychiatrist, described together the clinical symptoms of presenile dementia and the pathologic findings of amyloid plaques and neurofibrillary tangles, based on clinical records and autopsy of patient Auguste D. Four years later, in 1910, Dr. Emil Kraepelin, an influential German psychiatrist, coined the name “Alzheimer’s Disease” for this disease, in the eighth edition of his textbook “Psychiatrie”. It wasn’t until 9 September 1993, however, or 86 years and 10 months following Dr. Alzheimer’s initial presentation, that the first drug specifically targeting symptoms of Alzheimer’s Disease was approved, the acetylcholinesterase inhibitor Cognex (tacrine).

Drug Approvals

There have been a total of six drugs approved for the treatment of Alzheimer’s Disease, not including new formulations of previously approved drugs (click on Alzheimer’s Disease). The pharmacologic classes of the approved drugs for the treatment of patients with different stages of dementia of the Alzheimer’s type are only two, acetylcholinesterase inhibitors and NMDA antagonists:

  • Acetylcholinesterase Inhibitors: 4 NME’s, i.e., Cognex (tacrine); Aricept (donepezil), Exelon (rivastigmine), and Razadyne (galantamine); registration interest spans 7 years and 5 months, from 1993 to 2001. Note that the first of these drugs, Cognex (tacrine), has been discontinued.
  • NMDA Antagonists: 1 NME, i.e., Namenda (mematine); approval in 2003.
  • Combination products: 1 non-NME, i.e., Namzaric (donepezil + memantine); approval in 2014. Note that this it not an NME, since both active components had been previously approved.

It should be noted that Hydergine (ergoloid mesylates), first approved on 18 January 1953, has been used in the past for treating patients with dementia or ‘age-related’ cognitive symptoms, although it has not been approved for the treatment of symptoms of Alzheimer’s Disease.

Therapeutic Activity

All three current acetylcholinesterase inhibitors (Aricept, Exelon, Razadyne) are approved for the treatment of mild to moderate dementia of the Alzheimer’s type, and one (Aricept) is also approved for the treatment of moderate to severe dementia of the Alzheimer’s type. The other two approved drugs (Namenda, Namzaric) are approved for the treatment of moderate to severe dementia of the Alzheimer’s type. The registration (Phase III) trials for these agents have used similar assessment scales, i.e., ADAS-cog (the cognitive subscale of the Alzheimer’s Disease Assessment Scale) and CIBIC-plus (Clinician’s Interview-Based Impression of Change with caregiver information) for mild to moderate, and ADCS-ADL (Alzheimer’s Disease Cooperative Study – Activities of Daily Living) and SIB (Severe Impairment Battery) for moderate to severe. In general, the therapeutic effects of these agents were modest, and both the active treatments and the placebo treatments showed a wide range of responses, but the active treatments were more likely to show the greater improvements.


Two issues are worth commenting on in the context of approved treatments for Alzheimer’s Disease. First, the most recent approval (Namzaric) involves a combination product of two previously approved drugs. Considering the current development challenges in this area (many failed development programs and failed mechanisms of action), the high unmet medical need, and that the effects of the approved drugs are not considered to significantly affect disease progression, although delaying cognitive decline, one wonders what other chronic diseases, where there has been limited development progress, might be ripe for new combination products of previously approved drugs. For example, for obesity, where there has been a paucity of new therapeutic approaches and high unmet medical need, two of the four drug approvals since 1999 (Contrave, Qsyma), have involved combination products of previously approved drugs (1). A systematic and comprehensive review of other therapeutic classes will undoubtedly identify several other diseases where similar situations exist, including for other Psychopharmacologic and Neurologic Therapeutics.

Second, if recent history of progression of modern therapeutics is any guide, it is not unlikely that will take many years until there are next generation(s) of new NME drug approvals for Alzheimer’s Disease, including more than one per each new pharmacologic class. We note that the average number of pharmacologic classes per therapeutic class for 25 therapeutic classes that have been looked at is 4 (ranging from 1 to 10), and that the number of new NME drug approvals per pharmacologic class ranges widely, from 1 to 14 (2). We also note that the length of registration interest, defined here as the length of time from the first approval to the latest approval within a give pharmacologic class, has varied tremendously, ranging from a year or two to over 40 years (2). Thus, based on recent NME approval history of 25 therapeutic classes, and assuming there are one or more new breakthrough pharmacologic classes in the pipeline, and assuming more than one new NME drug approval per pharmacologic class, unfortunately, it is likely to take many years until we have a markedly different therapeutic choices for Alzheimer’s Disease. One hopes meaningful progress will have occurred before the 120th anniversary of Dr. Alois Alzheimer’s initial presentation.


  1. Weight Reduction Drugs: Slow Progression and Innovation (https://tri-institute.org/?p=394).
  2. Progression of Modern Therapeutics (2014 version), pages 33-35 (Progression of Modern Therapeutics (2014 Report))

Refer to page 23 of Progression of Modern Therapeutics (2014 Report) available under Reports on this website; this Report also includes the methodology used.