As the path to disease eradication continues, the contribution of pharmaceutical companies is increasingly important. These companies have been instrumental in developing treatments and cures for a wide range of illnesses that were previously debilitating or even deadly.
The U.S. pharmaceutical industry statistics show that the market size is $560 billion, with 4.76 billion prescriptions filled each year, projected to grow at a 6.3% CAGR through 2028. In this article, we will explore the most prominent pharmaceutical companies in the U.S., including their primary keywords, revenue, and breakthroughs.
Pfizer is the biggest pharmaceutical company in the United States by revenue. The company is known for its drug called Lipitor, which became the world’s best-selling drug in 2010.
Lipitor is a cholesterol-lowering medication that reduces the risk of heart attacks and strokes. Other notable drugs developed and marketed by Pfizer include Viagra, the erectile dysfunction treatment, and Prevnar, a pneumococcal vaccine that prevents infections such as meningitis.
Lipitor is a statin drug that blocks the production of cholesterol in the liver. Research has shown that cholesterol is a significant factor in the development of heart disease.
Therefore, Lipitor has been instrumental in reducing the number of heart attacks and strokes globally. In 2019, Pfizer generated over $51.8 billion in revenue.
2. Johnson & Johnson
Primary Keyword(s): healthcare, medical devices
Johnson & Johnson is a healthcare and medical device manufacturing company that deals in consumer health products, medical devices, and pharmaceuticals.
The company has been a leader in the healthcare industry since it was founded more than 130 years ago. Johnson & Johnson is known for its consumer products, including baby shampoo and pain relief medications, such as Tylenol.
The company’s pharmaceutical arm is Janssen Pharmaceuticals, which is a leader in developing treatments for chronic diseases like diabetes, autoimmune diseases, and cancer. A notable example of their medical breakthroughs is Darzalex, a monoclonal antibody used to treat multiple myeloma, a cancer of plasma cells in the bone marrow.
In 2019, Johnson & Johnson’s total revenue was $82.1 billion. 3.
Merck & Co.
Primary Keyword(s): vaccines, treatments
Merck & Co. is a pharmaceutical company based in New Jersey that focuses on developing and producing vaccines, therapies, and animal health products. Merck is known for creating vaccines, including the human papillomavirus (HPV) vaccine Gardasil, which is expected to prevent around 90% of cervical cancers.
Other notable drugs developed and marketed by Merck include Keytruda, an immunotherapy drug that helps the immune system fight cancer cells, and a diabetes medication called Januvia. Merck has developed many drugs that have undoubtedly saved countless lives and transformed medical care.
In 2019, the company’s total revenue was $45.8 billion. 4.
AbbVie
Primary Keyword(s): bioresearch, specialty therapeutics
AbbVie is a bio-research company focused on discovering, developing, and producing treatments for chronic diseases, including rheumatoid arthritis, psoriasis, and cancer. AbbVie has several successful brands, including the arthritis medicine Humira, which is the best-selling drug in the world.
Humira works by reducing inflammation in the body. Another notable breakthrough by this company is Imbruvica, a drug that is used as a targeted therapy for patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or mantle cell lymphoma.
AbbVie’s 2019 revenue was $33.3 billion. 5.
Amgen
Primary Keyword(s): biotechnology, biosimilars
Amgen is a biotechnology company that develops and produces innovative treatments for cancer, kidney disease, rheumatoid arthritis, and other life-threatening illnesses. The company’s primary focus is on producing therapeutic proteins to create groundbreaking medicines for patients globally.
In 2019, Amgen launched its biosimilar versions of drugs, including the cancer drug Herceptin and the arthritis drug Enbrel. The company is also known for producing drugs like Blincyto, a treatment for acute lymphoblastic leukemia, and Prolia, a treatment for osteoporosis in postmenopausal women.
Amgen’s 2019 revenue was $23.4 billion. 6.
Bristol-Myers Squibb
Primary Keyword(s): cancer research, medication development
Bristol-Myers Squibb is a pharmaceutical company that focuses on developing drugs for cancer and immunology. The company has several successful brands, including Opdivo, an immunotherapy drug used to treat melanoma, non-small cell lung cancer, and kidney cancer.
In 2019, Bristol-Myers Squibb acquired Celgene, strengthening the company’s position in the market for cancer treatments. Celgene’s contribution to the deal was a pipeline of oncology drugs in development.
The company’s 2019 revenue was $26.1 billion. 7.
Eli Lilly and Company
Primary Keyword(s): diabetes research, neuroscience
Eli Lilly and Company is a pharmaceutical company that focuses on developing and marketing drugs for diabetes, neuroscience, cancer, and immunology. Lilly’s most recognized drug is Humalog, which is a fast-acting insulin used to treat diabetes.
It is the first insulin analog to be approved by the FDA. Lilly has invested heavily in neuroscience research, and it has produced several promising treatments for Alzheimer’s disease.
The company’s drug, Solanezumab, is a promising drug that has been shown to help stop the progression of Alzheimer’s in patients. In 2019, Eli Lilly’s total revenue was $22.3 billion.
8. Gilead Sciences
Primary Keyword(s): antiviral drugs, immunology
Gilead Sciences is a biopharmaceutical company that focuses on developing and producing treatments for viral diseases, oncology, and cardiovascular diseases.
The company’s breakthrough contribution is its antiviral drugs, such as its hepatitis drug called Sovaldi, which cures the disease in more than 90% of people who complete the full treatment course. Additionally, Gilead Sciences has developed Veklury, an antiviral medication used to treat COVID-19.
The company’s revenue in 2019 was $22.4 billion. 9.
Novartis
Primary Keyword(s): oncology, gene therapy
Novartis is a Swiss-based pharmaceutical company that specializes in developing drugs for oncology, immunology, and neurology. The company’s most notable breakthroughs are its CAR-T cell therapies, which reprogramme a patient’s immune system to attack cancer cells.
Kymriah, one of Novartis’s drug, is a CAR-T cell therapy that is used to treat children with acute lymphoblastic leukemia. The company’s 2019 revenue was $45.5 billion.
10. Sanofi
Primary Keyword(s): vaccination, diabetes
Finally, Sanofi is a multinational pharmaceutical company based in France that produces vaccines, cardiovascular disease treatments, and diabetes medications.
Sanofi’s vaccination program is extensive and includes vaccines for polio, hepatitis, and seasonal influenza. The company’s biggest-selling drug category are diabetes treatments.
Sanofi’s breakthrough drug is Lantus, an insulin therapy for people with diabetes. It was the world’s best-selling insulin until recently.
In 2019, Sanofi’s total revenue was $40.7 billion. In conclusion, these pharmaceutical companies’ contributions to medical and scientific research show the impact of the pharmaceutical sector on public healthcare across the globe.
These companies’ achievements in creating, marketing, and developing lifesaving drugs are groundbreaking, and their ongoing efforts to create new treatments continue to be crucial steps toward achieving a healthier, improved society. 2.
Johnson & Johnson – Largest Pharmaceutical Company
Johnson & Johnson is the world’s largest pharmaceutical company by revenue. As a multinational corporation, it operates in the realms of medical devices, consumer healthcare, and pharmaceuticals.
The company’s brands include Band-Aid, Neutrogena, and Listerine, so consumers are likely familiar with some of the products they manufacture. With their roots going back to the 19th century, Johnson & Johnson is an established and successful company and has been ranked as one of the top places to work in the United States.
One of the company’s greatest breakthroughs was the development of the first commercially viable sterile surgical suture back in 1887. Sterile sutures revolutionized the medical world at that time, enabling patients to receive safe surgeries without the risk of infections.
Today, Johnson & Johnson continues to innovate with their Advanced Surgery portfolio, which includes a diverse range of products, from surgical staplers and adhesive materials for internal use to advanced techniques for wound care. In the pharmaceutical arena, Johnson & Johnson’s drug Zytiga is one of the most successful cancer drugs worldwide, generating over $2 billion in sales yearly.
Zytiga is a vital medication used in treating prostate cancer, among other types of cancer. Additionally, the company’s immunology portfolio includes Stelara, a medicine that targets various immune molecules and is prescribed for psoriatic arthritis and Crohn’s disease.
Johnson & Johnson’s primary focus in research and development is on creating cutting-edge medical devices and drugs to fight the world’s most challenging diseases. The company is continually utilizing recent scientific discoveries to enhance patient care, focusing on disease prevention along with cures.
Johnson & Johnson’s global reach is unmatched, with a presence in over 60 countries around the world. Through both the development and acquisition of new technologies and treatments, the company has positioned itself as a leader in the healthcare industry.
3. AbbVie – Crohn’s Disease and Cystic Fibrosis
AbbVie is a pharmaceutical company focused on developing and producing life-changing treatments for a variety of chronic conditions, including Crohn’s disease and cystic fibrosis.
Crohn’s disease is a chronic inflammatory disease that primarily affects the digestive tract. Researchers and physicians have identified an immune system abnormality that leads to chronic inflammation contributing to various ulcers, scarring, and fissures within the gastrointestinal tract, leading to significant discomfort.
AbbVie developed and produces the medication Humira, one of the first biologic therapies available to treat Crohn’s disease. Humira works by binding to a protein in the body that is responsible for the inflammation caused by Crohn’s disease.
In 2019, AbbVie generated revenue of $19.5 billion, with Humira contributing a significant portion of that revenue. Cystic Fibrosis is a genetic disease that affects the respiratory and digestive systems, leading to lung and digestive system damage.
AbbVie, in partnership with Vertex Pharmaceuticals, has developed a breakthrough drug, Kalydeco, which was the first FDA-approved drug to treat the underlying causes of cystic fibrosis. Kalydeco is a medication that works on a particular genetic mutation to improve the function of the affected protein.
Another medicine developed by AbbVie and Vertex Pharmaceuticals is Trikafta, a drug that treats the underlying causes of cystic fibrosis and has been shown to improve lung function. In 2019, Trikafta generated over $3 billion in sales, with AbbVie’s total revenue in the same year reaching $33.3 billion.
AbbVie focuses on discovering and developing innovative biopharmaceuticals that aim to improve patient outcomes through a range of medical treatments. The company has a broad array of products that address various areas of need, including cancer, autoimmune disorders, gastroenterology, and dermatology.
In conclusion, AbbVie and Johnson & Johnson are two of the most prominent pharmaceutical companies globally, focused on developing innovative medical devices and treatments for numerous chronic conditions. AbbVie’s work on Crohn’s disease and cystic fibrosis has significantly benefited patients, while Johnson & Johnson’s widespread presence in healthcare has enabled it to achieve massive success and become the largest pharmaceutical company in the world.
With continuous research and development into various illnesses, both companies have proven their commitment to advancing patient care and saving lives. 4.
Bristol-Myers Squibb – Quality Control Standards
Bristol-Myers Squibb is a pharmaceutical company that focuses on developing treatments for cancer and immunology. An essential aspect of their operations is the maintenance of high-quality control standards in the manufacturing and distribution of their products.
Bristol-Myers Squibb adheres to strict quality control standards at every stage of drug development and manufacturing. From material selection to processing, labelling, and packaging, checkpoints are established to ensure that drugs meet the required standards for safety, efficacy, and quality.
The company goes beyond regulations set by governing bodies such as the FDA, implementing strict internal controls to ensure their products meet or exceed industry standards. They achieve this through various methods, including reviewing manufacturing processes, sampling, testing, and validation.
The internal measures are continuously monitored through regular audits and evaluations to maintain high-quality standards. Additionally, Bristol-Myers Squibb utilizes sophisticated technology, including state-of-the-art analytical equipment and statistical techniques, to ensure that their drugs meet the targeted specifications.
The company takes pride in ensuring a high level of product consistency and reliability through the establishment of standardized procedures for every stage of a drug’s development. Through a commitment to rigorous quality control standards, Bristol-Myers Squibb has earned a reputation for maintaining the highest quality standards in the pharmaceutical industry.
5. Abbott – Diagnostic and Medical Technology
Abbott is a global healthcare company that specializes in medical devices, diagnostics, nutrition, and branded generic medicines.
The focus of their research and development is to deliver innovative solutions to improve patient outcomes globally. The company’s leading-edge diagnostic technology, including lab equipment, point-of-care systems, and molecular testing solutions, have transformed how healthcare providers diagnose and manage a variety of diseases.
Some of their notable technologies include the i-STAT system, which provides real-time blood analysis at the patient bedside, and the architect system, which is used in clinical laboratory testing. Abbott’s focus in medical technology extends beyond diagnostics, with a wide range of medical devices aimed at improving the quality of life for patients.
These devices include implantable cardiac products, neuromodulation devices, and diabetes care products. For example, their FreeStyle Libre glucose-monitoring system uses a small sensor inserted under the skin that needs to be worn for fourteen days to provide continuous glucose monitoring data.
This technology eliminates the need for traditional blood sampling from patients with diabetes. It is a game-changer for those living with diabetes, as it provides real-time information about their glucose levels, allowing patients to manage their treatment proactively.
Abbott’s medical technology solutions have been awarded several patents and accolades for their innovative design and patient-focused approach. The company’s commitment to technological advancements has enabled it to remain at the forefront of the healthcare industry globally.
In conclusion, Bristol-Myers Squibb and Abbott are two of the leading players in the pharmaceutical and medical technology sectors, respectively. Through their continued drive to innovate and improve the quality of life for patients, Bristol-Myers Squibb’s adherence to quality control standards and Abbott’s cutting-edge diagnostic and medical technology have transformed patient care.
Through their groundbreaking efforts, both companies have made it possible to tackle complex diseases and transform the healthcare industry profoundly. 6.
Merck & Co. – Gardasil and Fortune 500
Merck & Co., also known as Merck Sharp & Dohme (MSD) outside the United States and Canada, is a notable pharmaceutical company that focuses on developing vaccines, therapies, and animal health products. A significant achievement for Merck & Co. is the development of Gardasil, a breakthrough vaccine that protects against the human papillomavirus (HPV).
Gardasil is a game-changer in the field of vaccine development, particularly in the prevention of certain types of cancers. HPV is a sexually transmitted infection that can lead to various cancers, including cervical, anal, vulvar, and throat cancers.
By developing Gardasil, Merck & Co. created an effective means of preventing HPV infection and subsequently reducing the risk of associated cancers. The vaccine works by targeting specific HPV strains, helping the body develop immunity against them.
Gardasil has received widespread recognition for its impact on public health, particularly in the prevention of cervical cancer. In fact, it is estimated that the vaccine can potentially prevent around 90% of cervical cancers worldwide.
In addition to the breakthrough success of Gardasil, Merck & Co. has had an illustrious history as a Fortune 500 company. The Fortune 500 list ranks the largest U.S. companies based on their revenues.
Merck & Co. has consistently made the list, highlighting its financial success and market influence. Merck & Co.’s inclusion in the Fortune 500 can be attributed to its diverse portfolio of pharmaceutical products.
The company has consistently delivered innovative solutions for a wide range of diseases and medical conditions. Aside from vaccines like Gardasil, Merck & Co. has developed pioneering drugs and therapies for various ailments, including cardiovascular diseases, diabetes, oncology, and infectious diseases.
The company’s success is not solely based on its revenue and market positioning. Merck & Co. has also demonstrated a commitment to corporate social responsibility and sustainability.
In recent years, the company has focused on reducing its environmental footprint, promoting diversity and inclusion, and investing in communities to improve healthcare access.
Eli Lilly and Company – Mass-Producing Drugs and Recombinant DNA
Eli Lilly and Company, a global pharmaceutical company, has been at the forefront of mass-producing drugs and utilizing recombinant DNA technology to advance medical treatments. Mass production of drugs involves the large-scale manufacturing of pharmaceutical products to ensure sufficient supply for patients worldwide.
Eli Lilly has developed highly optimized manufacturing processes and capabilities that enable the rapid, efficient, and cost-effective production of drugs on a large scale. One of the most significant milestones in Eli Lilly’s journey of mass production was the development of insulin.
Insulin is a vital hormone used to regulate blood sugar levels in individuals with diabetes. Eli Lilly played a crucial role in making insulin widely accessible by developing efficient methods to mass produce this life-saving drug.
The company’s commitment to ensuring a stable supply of insulin has significantly improved the lives of millions of people living with diabetes worldwide. Furthermore, Eli Lilly has been at the forefront of harnessing recombinant DNA technology in drug development.
Recombinant DNA technology involves the manipulation and combination of DNA molecules from different sources to create novel genetic material. This technology has revolutionized the pharmaceutical industry by enabling the production of therapeutic proteins and biologics.
Eli Lilly’s expertise in recombinant DNA technology has led to the development of groundbreaking therapies. For example, the company’s drug, Humulin, is a biosynthetic human insulin produced using recombinant DNA technology.
This innovation provides a safe and effective alternative to animal-derived insulin. Eli Lilly has also utilized recombinant DNA technology to create a range of other biologic drugs, including monoclonal antibodies and other protein-based therapies.
The utilization of recombinant DNA technology has also enabled Eli Lilly to explore new avenues of drug discovery and development. By manipulating genetic material, scientists at the company can create novel proteins with therapeutic potential, opening new doors for the treatment of various diseases.
In conclusion, both Merck & Co. and Eli Lilly and Company have made significant contributions to the pharmaceutical industry through their groundbreaking advancements. Merck’s development of Gardasil has revolutionized cancer prevention, particularly in relation to HPV-related cancers.
Meanwhile, Eli Lilly’s focus on mass-producing drugs and utilizing recombinant DNA technology has allowed for improved accessibility to life-saving medications and opened new horizons in therapeutic development. Through their continued commitment to innovation and patient care, these companies have made a lasting impact on global healthcare.
8. Stryker – Implants and Medical Devices
Stryker Corporation is a global leader in the development and manufacturing of innovative medical devices and implants.
The company specializes in a wide range of products, from orthopedic implants and surgical instruments to medical equipment used in various specialties such as neurosurgery, spine, and trauma. One of Stryker’s notable areas of expertise is orthopedic implants.
The company designs and manufactures a comprehensive range of implants for joint replacement surgeries, including hip, knee, and shoulder replacements. These implants are carefully engineered to provide optimal functionality, durability, and compatibility with the patient’s anatomy.
Stryker’s joint replacement systems aim to improve patients’ quality of life by alleviating pain, restoring mobility, and enhancing overall joint function. Moreover, Stryker has made significant advancements in the field of medical devices for minimally invasive surgeries.
Through the development of specialized instruments and technologies, Stryker enables surgeons to perform complex procedures with greater precision, reduced invasiveness, and faster recovery times. These advancements have revolutionized surgical techniques and patient outcomes in various specialties, such as spine surgery and neurosurgery.
In addition to implants and surgical instruments, Stryker offers a diverse range of medical equipment and technologies that support different medical disciplines. The company’s offerings include advanced imaging systems, patient handling equipment, endoscopy devices, and surgical navigation systems.
These technologies enable healthcare professionals to diagnose, treat, and monitor patients more effectively, leading to improved outcomes and better patient care. Stryker’s commitment to innovation and quality has earned the company numerous accolades, including recognition for its patient-centric approach and dedication to improving healthcare delivery.
With a strong focus on research and development, Stryker continues to push the boundaries of medical device technology, seeking constant improvement in patient outcomes and healthcare efficiency. 9.
Biogen – Hemophilia and Multiple Sclerosis
Biogen is a leading biotechnology company that focuses on developing innovative therapies for neurological and hematological conditions. The company’s primary areas of expertise lie in the treatment of hemophilia and multiple sclerosis (MS).
Hemophilia is a rare genetic disorder that impairs the body’s ability to form blood clots. This can result in prolonged bleeding, both internally and externally, leading to severe complications.
Biogen has developed therapies that address this blood disorder, providing relief and improving the quality of life for those affected. One of Biogen’s breakthrough treatments for hemophilia is Eloctate, a recombinant clotting factor VIII therapy for both children and adults with hemophilia A.
Eloctate utilizes extended half-life technology to reduce the frequency of treatment administration, allowing patients to maintain more stable clotting factor levels and reducing the risk of bleeding episodes. Biogen has also made significant contributions to the field of multiple sclerosis.
Multiple sclerosis is a chronic autoimmune disease that affects the central nervous system, leading to a range of symptoms, including muscle weakness, fatigue, and cognitive impairment. Biogen has developed several disease-modifying therapies that have shown efficacy in reducing the frequency and severity of relapses, slowing disease progression, and improving patient outcomes.
One of Biogen’s most well-known products for multiple sclerosis is Tysabri. Tysabri is a monoclonal antibody that inhibits specific immune cells from attacking the myelin sheath, the protective covering of nerve fibers.
By controlling the immune response, Tysabri helps reduce the inflammation and damage caused by multiple sclerosis, leading to a reduction in relapses and disease activity. The development of therapies for hemophilia and multiple sclerosis is a complex and lengthy process, involving extensive research, clinical trials, and regulatory approvals.
Biogen’s commitment to scientific excellence, clinical innovation, and collaboration with healthcare professionals and patient communities has been instrumental in advancing the understanding and treatment of these debilitating diseases. In conclusion, Stryker and Biogen demonstrate the power of medical device innovation and biotechnology in improving patient care.
Through Stryker’s development of implants and medical devices, patients can benefit from the latest advancements in orthopedic surgery and minimally invasive procedures. Biogen’s focus on neurological and hematological conditions, particularly hemophilia and multiple sclerosis, highlights the company’s commitment to developing innovative therapies that enhance the lives of patients.
With their dedication to research, development, and patient-centric care, both Stryker and Biogen are making significant contributions to advancing healthcare and improving patient outcomes. 10.
Importance of Pharmaceutical Company Services
Pharmaceutical companies play a pivotal role in society by developing, testing, manufacturing, marketing, and distributing drugs that improve and save lives. These companies face various challenges throughout the drug development process but provide invaluable services that contribute to advancements in medicine and patient care.
One of the most significant challenges pharmaceutical companies face is the complex and expensive process of creating new drugs. Developing a new drug involves extensive research, including identifying potential therapeutic targets, conducting preclinical studies, and navigating the rigorous requirements of regulatory authorities such as the FDA.
It can take a significant investment of time and money, often spanning several years and costing billions of dollars to bring a new drug to market. The importance of creating new drugs cannot be overstated.
Pharmaceutical companies focus their research efforts on addressing unmet medical needs, discovering solutions to diseases for which there are no or limited treatment options. By developing new drugs, these companies provide hope to patients facing life-threatening or debilitating conditions, improving their quality of life and extending their lifespan.
For example, the development of targeted therapies for cancer has revolutionized cancer care, allowing for more precise treatments and better patient outcomes. Once a drug is developed, it must undergo rigorous testing to ensure safety and efficacy.
Clinical trials, which involve testing the drug on human volunteers, are critical for determining its therapeutic benefits, dosage, potential side effects, and interactions with other medications. Pharmaceutical companies design and conduct these trials in compliance with strict ethical and regulatory guidelines, working closely with healthcare professionals and patients to gather data and assess the drug’s performance.
The marketing and distribution of drugs are also vital components of the pharmaceutical industry. Pharmaceutical companies employ sales and marketing teams to educate healthcare professionals about the benefits of their medications, ensuring that doctors have the necessary information to make informed decisions about prescribing the drugs to their patients.
Effective marketing efforts are essential in raising awareness about available treatment options, empowering patients to seek appropriate care and adhere to prescribed treatments. The distribution of drugs requires a robust supply chain and logistical infrastructure to ensure that medications reach healthcare providers and patients in a timely manner.
Pharmaceutical companies work closely with wholesalers, distributors, and pharmacies to coordinate the safe and efficient delivery of drugs. This process involves adhering to stringent quality control standards, managing inventory, and monitoring product expiration dates to maintain medication efficacy.
The pharmaceutical industry presents a high barrier for entry due to the complex and highly regulated nature of the work. The rigorous requirements for drug development, testing, and approval serve as safeguards to protect patient safety and ensure that only safe and effective drugs enter the market.
This high entry barrier is necessary to maintain the integrity of the industry and prevent substandard or potentially harmful drugs from reaching consumers. Additionally, the pharmaceutical industry is highly competitive.
Companies must continuously innovate and invest in research and development to stay ahead in the market. Developing new drugs requires a deep understanding of scientific research, medical knowledge, and cutting-edge technologies.
Pharmaceutical companies employ teams of researchers, scientists, and experts who collaborate to pursue breakthroughs and advancements in medicine. In conclusion, pharmaceutical companies play a vital role in society’s well-being by creating, testing, manufacturing, marketing, and distributing drugs.
Despite the challenges they face, these companies provide essential services that drive progress in medicine and patient care. Their contributions lead to the development of innovative treatments, improved outcomes for patients, and advancements in medical knowledge.
The pharmaceutical industry’s high barrier for entry and competitive landscape reflect the importance of maintaining quality and ensuring patient safety, while continuous innovation propels the industry forward.
3) Top 10 Largest Pharmaceutical Companies
The pharmaceutical industry is vast and diverse, with numerous companies making significant co