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THE DRUG DEVELOPMENT PROCESS AND THE GLOBAL PHARMACEUTICAL MARKETPLACE

1.1 INTRODUCTION

Pharmaceuticals are a global industry, grossing $1.25 trillion (US dollars) in 2019. They are developed to benefit (and sell to) individuals and societies worldwide. Their effectiveness and costs affect, directly or indirectly, all of us.

This fourth edition focuses (as its predecessors did) on the assessment of the safety of new drugs. In the broadest sense, this means it must address not only the traditional "small molecules" that have dominated the field for the last century and the large therapeutic molecules derived from biotechnology sources but also vaccines, biologics such as blood and blood products, cell therapies, and excipients. The globalization of the regulation of the safety, efficacy, and manufacture of pharmaceutical products comes from the success of the International Conference on Harmonization (ICH) process. But, as will be seen, the same globalization of the industry and continuous advances of science have also led to market diversification of the types and uses of drugs, and with this, regulatory drug safety evaluation requirements continue to fragment, which has made things more complex rather than simpler (Alder and Zbinden, 1988; Gad, 2018; Norman 2016a, 2016b).

1.2 THE MARKETPLACE

The world marketplace for drugs is large, although the majority of sales are in three regions: in 2019 about 35% of the pharmaceutical market (by sales) resided in the United States, 24% in Europe, 12% in Japan, with the remaining 29% in emerging markets (Christel, 2019). This does not mean, however, that marketing applicants can or should ignore the requirements of other countries, for example, China and Indonesia. Approval processes in these countries can at times be as rigorous as in any other regulatory authority's domain.

Pharmaceuticals in all their forms compete today as part of a global market, though one which serves (and is available to) different parts of the world's population to varying extents.

The term "pharmaceuticals" is here used in the broadest sense of man-made therapeutics: small molecules, large protein moieties, vaccines, blood products, and as must be, their attendant components (excipients, impurities, and all) to different degrees and in different types of products.

According to the Statista (2019) global pharmaceutical market and therapy report, the global market for regulated drugs (as differentiated from dietary supplements, herbal products, and nutraceuticals) is estimated to have been some $1.25 trillion in 2019 (US dollars) (Drugs.com, 2014). In 2015, there were 143 individual products with annual sales in excess of $1 billion (i.e., "blockbusters") which have tended to be the focus of pharmaceutical development until recently and the impending demise of patents on which is changing the industry (Table 1.1). It remains to be seen how the Covid-19 pandemic influences 2020 and 2021 statistics.

This concentration of total sales in a limited number of products (e.g., there are currently more than 22?000 approved prescription drugs in the United States) is widely held to have distorted the therapeutic aspects of new drug development but is now starting to undergo change (back to) a paradigm that looks at a decreased emphasis on the billion dollar "blockbuster" drugs.

Widely misunderstood is the extent and diversity of the pharmaceutical R&D sector. While precise numbers are unavailable (and meaningless, as companies are continuously being started, merged, or going out of business, though the overall trend is to increased numbers), best estimates place the number of companies directly involved in discovering and developing new drugs in the United States and Canada at about 3800, 10% of which are publicly traded. There are an equal number in Europe and significant numbers in many other parts of the world (Japan, China, Australia, India, and Israel, to name just a few other countries). While most of the public focuses on very large companies, such as those in Table 1.2, there are many more midsize and small companies.

TABLE 1.1 Top 20 Selling Pharmaceuticals (2019) (Sharma, 2020)

Source: pharmashots.com (2020).

Rank Drug Current manufacturer Total sales 2019 Total sales 2018 Total sales 2017 Primary disease/medical use Route(s) In billions, USD 1 Humira (adalimumab) AbbVie, Inc. and Elsai 19.16 20.3 Not available Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, adult, and pediatric Crohn's disease, plaque psoriasis, juvenile idiopathic arthritis, ulcerative colitis, axial spondyloarthropathy (EU only), hidradenitis suppurativa, pediatric enthesitis-related arthritis (EU only), panuveitis, Behcet's disease (Japan only) Injection 2 Keytruda (pembrolizumab) Merck & Co. 11.08 7.17 3.8 Nonsmall cell lung cancer, melanoma, head, and neck squamous cell cancer, urothelial bladder cancer, kidney cancer, microsatellite instability-high cancer, classical Hodgkin lymphoma, gastric cancer, cervical cancer, primary mediastinal B-cell lymphoma, hepatocellular carcinoma, Merkel cell carcinoma Injection 3 Revlimid (lenalidomide) Bristol-Myers Squibb and Ono Pharmaceutical 9.37 9.69 8.19 Anemia, multiple myeloma, myelodysplastic syndromes, mantle cell lymphoma, follicular lymphoma Oral 4 Elquis (apixaban) Bristol-Myers Squibb 7.92 9.87 7.4 Reduce risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; deep vein thrombosis and pulmonary embolism Oral 5 Eylea (aflibercept) Regeneron Pharmaceutical, Bayer, Saten Pharmaceutical 7.54 7.16 6.39 Neovascular (wet) age-related macular degeneration, macular edema following central retinal vein occlusion, diabetic macular edema, diabetic retinopathy Intraocular 6 Avastin (bevacizumab) Roche, Chugai Pharmaceutical 7.3 7 6.8 Anti-angiogenic, brain tumor, certain types of cancers of the kidney, lung, colon, rectum, cervix, ovary, or fallopian tube. Cancer of the membrane lining the internal organs in the abdomen IV 7 Opdivo (nivolumab) Bristol-Myers Squibb, Ono Pharmaceutical 7.2 7.55 5.76 Melanoma, nonsmall cell lung cancer, small cell lung cancer, renal cell carcinoma, classical Hodgkin lymphoma, squamous cell carcinoma of the head and neck, urothelial carcinoma, colorectal cancer, hepatocellular carcinoma IV 8 Rituxan/MabThera (Rituximab) Roche, Chungai Pharmaceutical, Zenyaku Kogyo 6.9 6.9 7.55 Non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis, pemphigus vulgaris, B-cell lymphoproliferative disorders (Japan), pediatric nephrotic syndrome (Japan) IV 9 Stelara (ustekinumab) Johnson & Johnson 6.36 5.16 4 Plaque psoriasis, Crohn's disease, psoriatic arthritis Injection 10 Herceptin (trastuzumab) Roche, Chugai Pharmaceutical 6.23 7.14 7.17 Breast cancer IV 11 Prevnar 13/Prevenar 13 (pneumococcal conjugate vaccine) Pfizer, Daewoong Pharmaceutical 5.84 5.8 5.69 Vaccine, pneumococcal disease, and pneumococcal pneumonia Injection 12 Enbrel (etanercept) Amgen, Pfizer, Takeda Pharmaceutical 5.22 7.13 8.23 Arthritis, or ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and polyarticular juvenile idiopathic arthritis Injection 13 Ibrance (Palbociclib) Pfizer 4.96 4.12 3.13 Breast cancer IV 14 Remicade (Infliximab) Johnson & Johnson, Merck, Mitsubishi Tanabe Pharma 4.36 6.44 7.73 Arthritis, ulcerative colitis, Crohn's disease, ankylosing spondylitis, plaque psoriasis IV 15 Genvoya (elvitegravir 150 mg/cobicstat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg) Gilead Sciences, Torii Pharmaceutical 3.93 4.69 3.73 HIV-1 infection Oral 16 Imbruvica (ibrutinib) Johnson & Johnson,...