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Development of Plant-Derived Mixtures as Botanical Drugs: Clinical Considerations

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The Science and Regulations of Naturally Derived Complex Drugs

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 32))

Abstract

In response to various drug -related disasters, the requirement for demonstration of safety for marketed drug products was first established in the Federal Food, Drug , and Cosmetic Act (FDCA) of 1938. The requirement for demonstration of a drug ’s effectiveness through adequate and well-controlled clinical investigations was added in the 1962 Kefauver-Harris Amendments of the FDCA. Since then, FDA has published several guidances which describe how clinical trials may be designed to adequately demonstrate the safety and efficacy of drug products and protect human subjects from unreasonable harms. FDA has issued Guidance for Industry on Botanical Drug Products (2004) and Botanical Drug Development (2016) that described how plant-derived mixtures, including multiple-herb combinations, may be developed as new drugs without further purification. Previous human experience may be used to support phase 2 clinical trials in patients, thus skipping “first-in-human” phase 1 tolerability studies. For drugs with prior human experience, animal toxicological studies may also be delayed to later phases of drug development . In phase 3 trials, patient exposure to multiple batches and multiple doses of botanical drug products is recommended in order to derive more reliable quality specifications and ensure therapeutic consistency for future marketed batches. Two botanical new drug applications (NDAs), Veregen ® (sinecatechins), for the treatment of genital warts), and Mytesi®, formerly Fulyzaq ® (crofelemer), for the treatment of HIV-related diarrhea, were approved by FDA in the past decade. The bases for these approvals will be described and will serve as successful examples to guide and encourage further development of botanicals as new drugs. Published clinical and nonclinical studies of two herbal medicines, Artemisia annua and Pelargonium sidoides , will be discussed to illustrate some of the challenges faced in clinical trial design and data reporting. Additional challenges in the development of botanical products derived from multiple herbs as fixed-dose drug combinations will also be discussed.

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Notes

  1. 1.

    Newman and Cragg [1].

  2. 2.

    Seewww.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

  3. 3.

    Seehttps://www.fda.gov/downloads/aboutfda/centersoffices/centerfordrugevaluationandresearch/ucm106136.pdf.

  4. 4.

    See http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM458484.pdf.

  5. 5.

    Wagner and Ulrich-Merzenich [2].

  6. 6.

    Elfawal and Towler [3].

  7. 7.

    Ettefagh et al. [4].

  8. 8.

    Bren [5].

  9. 9.

    FOOD AND DRUG ADMINISTRATION MODERNIZATION ACT OF 1997 (accessed at https://www.gpo.gov/fdsys/pkg/PLAW-105publ115/pdf/PLAW-105publ115.pdf on November 17, 2016).

  10. 10.

    See Footnote 2.

  11. 11.

    Sridhara [6].

  12. 12.

    Smithy et al. [7].

  13. 13.

    The Drug Development Process (accessed at http://www.fda.gov/ForPatients/Approvals/Drugs/ucm405622.htm#Clinical_Research_Phase_Studies on July 7, 2016).

  14. 14.

    Chen et al. [8].

  15. 15.

    Lee et al. [9].

  16. 16.

    21 CFR 300.50—Fixed-combination prescription drugs for humans (accessed at https://www.gpo.gov/fdsys/pkg/CFR-2011-title21-vol5/pdf/CFR-2011-title21-vol5-sec300-50.pdf on July 26, 2016).

  17. 17.

    See Footnotes 3 and 4.

  18. 18.

    See Footnotes 13 and 14.

  19. 19.

    FDA Guidance for Clinical Investigators, Sponsors, and IRBs Investigational New Drug Applications (INDs)—Determining Whether Human Research Studies Can Be Conducted Without an IND (September 2013) accessed online at http://www.fda.gov/downloads/Drugs/Guidances/UCM229175.pdf on July 15, 2016).

  20. 20.

    Chen [10].

  21. 21.

    Yoshikawa et al. [11].

  22. 22.

    Munekage et al. [12]

  23. 23.

    Itoh et al. [13].

  24. 24.

    https://clinicaltrials.gov/.

  25. 25.

    Huang et al. [14], Malar [15].

  26. 26.

    WHO, World Malaria Report 2015 (accessed at http://apps.who.int/iris/bitstream/10665/200018/1/9789241565158_eng.pdf on July 15, 2016).

  27. 27.

    Duke et al. [16].

  28. 28.

    Ferreira et al. [17].

  29. 29.

    Desrosiers and Weathers [18].

  30. 30.

    Wright et al. [19].

  31. 31.

    Rasoanaivo et al. [20].

  32. 32.

    Tamiflu® (oseltamivir phosphate) Capsules and for Oral Suspension (accessed at http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021087s033lbl.pdf on July 15).

  33. 33.

    EMA/HMPC/560961/2010. Community herbal monograph on Pelargonium sidoides DC and/or Pelargonium reniforme Curt., radix, 20 November 2012 (Accessed on line at http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Community_herbal_monograph/2013/02/WC500138439.pdf on November 4, 2016).

  34. 34.

    Timmer et al. [21].

  35. 35.

    Lizogub et al. [22].

  36. 36.

    Rizzi et al. [23]

  37. 37.

    Fu et al. [24].

  38. 38.

    Chang et al. [25]

  39. 39.

    Fixed-drug combinations https://www.gpo.gov/fdsys/pkg/FR-2015-12-23/pdf/2015-32246.pdf.

References

  1. Newman DJ, Cragg GM. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod. 2012;75(3):311–35.

    Article  CAS  Google Scholar 

  2. Wagner H, Ulrich-Merzenich G. Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine. 2009;16(2–3):97–110.

    Article  CAS  Google Scholar 

  3. Elfawal MA, Towler MJ, Reich NG, Weathers PJ, Rich SM. Dried whole-plant Artemisia annua slows evolution of malaria drug resistance and overcomes resistance to artemisinin. Proc Natl Acad Sci U S A. 2015;112(3):821–6.

    Article  CAS  Google Scholar 

  4. Ettefagh KA, Burns JT, Junio HA, Kaatz GW, Cech NB. Goldenseal (Hydrastis canadensis L.) extracts synergistically enhance the antibacterial activity of berberine via efflux pump inhibition. Planta Med. 2011;77(8):835–40.

    Article  Google Scholar 

  5. Bren L. The road to the biotech revolution—highlights of 100 years of biologics regulation. FDA Consumer magazine, The Centennial Edition. Jan–Feb 2006 (accessed on 16 Dec 2016 at http://www.fda.gov/AboutFDA/WhatWeDo/History/FOrgsHistory/CBER/ucm135758.htm).

  6. Sridhara R. Robert temple on trial design: adaptive and enrichment clinical trials come with pluses and pitfalls for researchers, accessed online at http://cancerdiscovery.aacrjournals.org/content/3/3/245.full.pdf+html on 15 July 2016.

  7. Smithy JW, Downing NS, Ross JS. Publication of pivotal efficacy trials for novel therapeutic agents approved between 2005 and 2011: a cross-sectional study. JAMA Intern Med. 2014;174(9):1518–20.

    Article  Google Scholar 

  8. Chen ST, Dou J, Temple R, Agarwal R, Wu KM, Walker S. New therapies from old medicines. Nat Biotechnol. 2008;26(10):1077–83.

    Article  CAS  Google Scholar 

  9. Lee SL, Dou JH, Agarwal R, Temple R, Beitz J, Wu C, Mulberg A, Yu LX, Woodcock J. Evolution of traditional medicines to botanical drugs. Science. 2015;347(6219 Suppl):S32–4.

    Google Scholar 

  10. Chen ST. Regulation of research: is it a drug trial or a supplement trial? Fitoterapia. 2011;82(1):14–6.

    Article  Google Scholar 

  11. Yoshikawa K, Shimada M, Wakabayashi G, Ishida K, Kaiho T, Kitagawa Y, Sakamoto J, Shiraishi N, Koeda K, Mochiki E, Saikawa Y, Yamaguchi K, Watanabe M, Morita S, Kitano S, Saji S, Kanematsu T, Kitajima M. Effect of Daikenchuto, a traditional Japanese herbal medicine, after total gastrectomy for gastric cancer: a multicenter, randomized, double-blind, placebo-controlled, phase II trial. J Am Coll Surg. 2015;221(2):571–8.

    Article  Google Scholar 

  12. Munekage M, Ichikawa K, Kitagawa H, Ishihara K, Uehara H, Watanabe J, Kono T, Hanazaki K. Population pharmacokinetic analysis of daikenchuto, a traditional Japanese medicine (Kampo) in Japanese and US health volunteers. Drug Metab Dispos. 2013;41(6):1256–63.

    Article  CAS  Google Scholar 

  13. Itoh T, Yamakawa J, Mai M, Yamaguchi N, Kanda T. The effect of the herbal medicine dai-kenchu-to on post-operative ileus. J Int Med Res. 2002;30(4):428–32.

    Article  CAS  Google Scholar 

  14. Huang SM, Temple R, Throckmorton DC, Lesko LJ. Drug interaction studies: study design, data analysis, and implications for dosing and labeling. Clin Pharmacol Ther. 2007;81(2):298–304.

    Article  CAS  Google Scholar 

  15. Malar J. 2011;10 Suppl 1:S4. https://doi.org/10.1186/1475-2875-10-s1-s4.

  16. Duke JA, Benge M, Cragg G, Ferreira J, Hopper J, Janick J, Kress WJ, Simon J, Strobel G, Weil A, Willcox ML. C&N News, 2 May 2005 (accessed online at http://cen.acs.org/articles/83/i18/herbal-solution.html on 15 July 2016).

  17. Ferreira JF, Luthria DL, Sasaki T, Heyerick A. Flavonoids from Artemisia annua L. as antioxidants and their potential synergism with artemisinin against malaria and cancer. Molecules. 2010;15(5):3135–70.

    Article  CAS  Google Scholar 

  18. Desrosiers MR, Weathers PJ. Effect of leaf digestion and artemisinin solubility for use in oral consumption of dried Artemisia annua leaves to treat malaria. J Ethnopharmacol. 2016;20(190):313–8.

    Article  Google Scholar 

  19. Wright CW, Linley PA, Brun R, Wittlin S, Hsu E. Ancient Chinese methods are remarkably effective for the preparation of artemisinin-rich extracts of Qing Hao with potent antimalarial activity. Molecules. 2010;15(2):804–12.

    Article  CAS  Google Scholar 

  20. Rasoanaivo P, Wright CW, Willcox ML, Gilbert B. Whole plant extracts versus single compounds for the treatment of malaria: synergy and positive interactions. Malar J. 2011;10(Suppl 1):S4.

    Article  Google Scholar 

  21. Timmer A, Günther J, Motschall E, Rücker G, Antes G, Kern WV. Pelargonium sidoides extract for treating acute respiratory tract infections. Cochrane Database Syst Rev. 2013;(10):CD006323.

    Google Scholar 

  22. Lizogub VG, Riley DS, Heger M. Efficacy of a pelargonium sidoides preparation in patients with the common cold: a randomized, double blind, placebo-controlled clinical trial. Explore (NY). 2007;3(6):573–84.

    Article  Google Scholar 

  23. Rizzi F, Naponelli V, Silva A, Modernelli A, Ramazzina I, Bonacini M, Tardito S, Gatti R, Uggeri J, Bettuzzi S. Polyphenon E(R), a standardized green tea extract, induces endoplasmic reticulum stress, leading to death of immortalized PNT1a cells by anoikis and tumorigenic PC3 by necroptosis. Carcinogenesis. 2014;35(4):828–39.

    Article  CAS  Google Scholar 

  24. Fu H, He J, Mei F, Zhang Q, Hara Y, Ryota S, Lubet RA, Chen R, Chen DR, You M. Lung cancer inhibitory effect of epigallocatechin-3-gallate is dependent on its presence in a complex mixture (polyphenon E). Cancer Prev Res (Phila). 2009;2(6):531–7.

    Article  CAS  Google Scholar 

  25. Chang PY, Mirsalis J, Riccio ES, Bakke JP, Lee PS, Shimon J, Phillips S, Fairchild D, Hara Y, Crowell JA. Genotoxicity and toxicity of the potential cancer-preventive agent polyphenon E. Environ Mol Mutagen. 2003;41(1):43–54.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Silver Spring, USA

    Jinhui Dou, Julie Beitz & Robert Temple

Authors
  1. Jinhui Dou
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  2. Julie Beitz
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  3. Robert Temple
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Corresponding author

Correspondence to Jinhui Dou .

Editor information

Editors and Affiliations

  1. Department of Biological Engineering, Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    Ram Sasisekharan

  2. Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA

    Sau L. Lee

  3. Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA

    Amy Rosenberg

  4. Director Emeritus, National Center for Natural Products Research, School of Pharmacy, University of Mississippi, Oxford, MS, USA

    Larry A. Walker

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Dou, J., Beitz, J., Temple, R. (2019). Development of Plant-Derived Mixtures as Botanical Drugs: Clinical Considerations. In: Sasisekharan, R., Lee, S., Rosenberg, A., Walker, L. (eds) The Science and Regulations of Naturally Derived Complex Drugs. AAPS Advances in the Pharmaceutical Sciences Series, vol 32. Springer, Cham. https://doi.org/10.1007/978-3-030-11751-1_14

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