The State of the Pharmaceutical Industry
Drugs have been used to treat ailments and injuries for thousands of years. Today, the pharmaceutical business is a multibillion dollar global industry. New and innovative treatments and medications are developed, manufactured, marketed, and distributed around the world on a regular basis.
A large part of the advances in healthcare have come out of the research and development of new drugs through the years. The healthcare and pharmaceutical industry serve to improve the overall quality of life of millions of people around the globe by providing vaccines, therapies, treatments, and medications for a wide range of medical conditions, issues, diseases, disorders, and more.
Roots of Pharmacology
Up until the late 18th century, herbal remedies and medicines were used because they were known to be effective; however, medical practitioners largely did not know how or why they worked. In the 1780s, William Withering was one of the first people to research an active ingredient from an herbal remedy when he discovered and isolated the active ingredient in the flowering foxglove plant digitalis.
The pharmacology industry continued to slowly inch along over the following century and beyond. Prior to the beginning of the pharmaceutical industry, pharmacists would often manufacture their own medications, and often, medicines were distributed directly from physicians without a prescription.
Companies such as Merck, Eli Lilly, and Roche supplied and distributed natural products like strychnine, morphine, and quinine. These companies began undertaking larger scale operations in the mid-19th century. The dyestuff and chemical companies Bayer, Sandoz, and Pfizer began researching medical applications for their products in newly created research labs.
Evolution of the Pharmaceutical Industry
One of the earliest and most influential medications to be synthesized was aspirin in 1897 by Dr. Felix Hoffman, a scientist for Bayer. The active ingredient in aspirin is acetylsalicylic acid, a synthetic form of salicylic acid, which had been used as far as back in the 5th century in the form of willow bark. By 1915, it was available without a prescription and quickly became a bestselling drug in the United States.
Insulin was another medical breakthrough around the same time. In 1922, it was discovered and developed to treat high blood glucose levels that accompany diabetes. Frederick Banting, Charles Best, and John Macleod are credited with the discovery and initial human trials for insulin, winning them the Nobel Prize in 1923.
Post-World War II brought many breakthroughs and advances in the pharmacology field. Between 1950 and the 1990s, new analgesics and antibiotics were developed. Novel classes of medications were discovered and manufactured, including oral contraceptives, ACE inhibitors, beta blockers, benzodiazepines, and completely new forms of anti-cancer treatments.
Notable Breakthroughs and Achievements in Pharmacology
- 1948: Sidney Farber discovers that aminopterin, a folic acid antagonist and chemotherapeutic agent, works to induce remission in children suffering from acute lymphocytic leukemia (ALL).
- 1950s: A freeze-dried and heat-stable version of the smallpox vaccine is developed. In the 1960s, American Home Products marketed Dryvax (vaccina) in the United States, paving the way for a future of vaccinations.
- 1955: Dr. Jonas Salk creates and gets the first polio vaccine – inoculated polio virus (IPV) – licensed for commercial use.
- 1961: The Boots Group in the UK develops the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen, which is marketed as Advil beginning in 1974.
- 1982: The first biosynthetic form of human insulin, Humulin, becomes commercially available, marketed by Eli Lilly. This is the first recombinant DNA drug on the market.
- 1989: Astra releases the first proton pump inhibitor (PPI) Prilosec (omeprazole) for the treatment of stomach acid and ulcers.
- 1997: Genentech and IDEC Pharmaceuticals get approval for Rituxan (rituximab), a biologic for the treatment of non-Hodgkin’s lymphoma.
- 1998: Remicade (infliximab), manufactured by Schering-Plough Corporation and Mitsubishi Tanabe Pharma Corporation, becomes the first anti-TNF-alpha treatment for treating Crohn’s disease and RA and helping over 1 million patients worldwide in less than a decade.
- 2001: GlaxoSmithKline (GSK) releases Advair (fluticasone propionate and salmeterol inhalation powder) in the US, a bronchodilator for asthma and chronic obstructive pulmonary disease (COPD).
How Medications Are Created and Approved
Pharmaceuticals are big business, and as such, companies are constantly striving to come up with medical and pharmacological breakthroughs. Medications are developed in labs by scientists and researchers. Medicine can be extracted from plants, made from biological materials, or synthesized chemically.
Research and Development of Medications
The first stage in developing a medication is experimental, investigational, and research-based, as scientists investigate new ways to use existing chemicals, manufacture new ones, or use new technologies. If a compound is deemed worth investigating further, more tests and research are done as it enters the preclinical stage, which generally includes animal testing and research involving safety of the potential drug.
Researchers perform “in vitro” or “in vivo” testing during the preclinical stage, and they are required to follow good laboratory practices (GLP) which set forth strict regulations and requirements. Preclinical trials do not need to be very large, but they must provide information on dosage and toxicity (potential of the drug to cause harm). If a drug shows promise through clinical trials, researchers will review the findings and possibly approve the drug to be tested in humans – the clinical research phase.
Clinical Research Phase of Medication Development
Clinical research involves sanctioned drug testing on groups of people to test the safety and efficacy of a new drug. Before clinical research can begin, researchers and drug developers must submit an application for an Investigational New Drug (IND) and get it approved by the FDA’s Center for Drug Evaluation and Research (CDER). The CDER review team contains scientific experts in various fields. The FDA has 30 days to review an IND before rendering a verdict and allowing it to proceed to the next phase of development: clinical research.
Clinical research has four phases:
- Phase 1: About 20-100 people, either people with the condition the drug is being tested for or healthy volunteers, are given the drug over a period of several months to test for safety and dosage. About 70 percent of drugs make it past this phase.
- Phase 2: Several hundred people suffering from the condition or disease are given the drug, over a period of months to up to two years, to test for side effects and efficacy. Around 33 percent of drugs make it through this phase.
- Phase 3: The testing is expanded to include 300-3,000 people with the condition or disease, and testing continues for 1-4 years to closely monitor adverse reactions and efficacy. About 25-30 percent of drugs make it past this phase.
- Phase 4: Several thousand volunteers with the condition or disease are tested with the drug to officially determine its safety and efficacy.
After two large and controlled clinical trials are completed, and a drug makes it through all four phases, while submitting research and results to the FDA along the way, the developer may file for a marketing application with a New Drug Application (NDA). The FDA review team has 6-10 months to look over an NDA after it is filed and decide whether to approve the drug. Sometimes, additional information or research is required prior to approval.
The FDA also engages in post-market safety monitoring, routinely inspects drug manufacturing plants, and regulates marketing and promotional labeling for the drug. Drugs are not legally allowed to be advertised for purposes other than what they have been approved to treat, and all advertising must be truthful, disclosing potential side effects and efficacy.
Major Legal Issues and Drug Recalls
The pharmaceutical industry has had many legal troubles, lawsuits, and drug recalls. One of the biggest disasters in pharmacology was thalidomide, which was heralded as a sleeping pill and cure for morning sickness in pregnant women all over Europe in the 1950s. Developed by Germany’s Chemie Grunenthal and marketed in the United State by William S. Merrell, thalidomide had a serious problem: It caused birth defects in babies born to mothers who took the drug while pregnant.
Notable Drug Recalls
- Tylenol (acetaminophen): In 1982, Johnson & Johnson pulled 31 million bottles of Tylenol from shelves after several people died after ingesting medication that had been altered and laced with cyanide. This was the first major recall of its kind and set the stage for future drug recalls.Tylenol was in the hot seat again in 2010, as Children’s Motrin (ibuprofen) and Infant’s and Children’s Tylenol were recalled again. In 2015, makers of the products, McNeil Consumer Healthcare (of Johnson & Johnson), pled guilty to selling the product despite knowledge that it contained metal bits.
- FenPhen (fenfluramine/phentermine): This was a common off-label treatment for obesity. American Home Products (AHP) Corporation marketed both Redux and Pondimin, which were found to cause heart valve disease and were recalled in 1997 after close to 25 years on the market. AHP agreed to pay nearly $4 billion in settlements to users of the products, one of the biggest product liability settlements at the time.
- Vioxx (rofecoxib): A painkiller made by Merck that was supposedly safer on the gastrointestinal system than its predecessor, Vioxx was on the market from 1999 until 2004 when it was pulled after many deaths and heart issues are reported. Merck paid out $4.85 billion to quell the thousands of lawsuits brought against them. Close to 90,000 people are reported to have suffered heart attacks as a result of taking Vioxx, and more than one-third of them died.
- Bextra (valdecoxib): This nonsteroidal anti-inflammatory drug (NSAID) made by Pfizer was pulled from the market in 2005 after three years of being marketed as a painkiller due to serious cardiovascular complications.
- Baycol (cerivastatin): This Bayer product for lowering cholesterol was recalled in 2001 after only three years on the market. Many deaths were reported, and the drug was found to cause life-threatening muscle destruction.
Legal Issues for Pharmaceutical Companies
Pharmaceutical companies are regularly involved in lawsuits as well. One company may sue another over patent rights, for example. Pharmaceutical companies have been hit with lawsuits claiming that they used unsavory, and potentially illegal, tactics to bar generic forms of their drugs from hitting the market.
Pharmaceutical companies have also been accused of Medicaid fraud, taking kickbacks, inflating profits, and downplaying side effects of a drug. Drugs may be illegally promoted or advertised to treat symptoms or disorders that they are not approved to treat.
Notable lawsuits and settlements involving pharmaceuticals include:
- Abilify (aripiprazole): A schizophrenia medication made by Bristol Meyers-Squibb was marketed for use in children and the elderly; this was not something it was approved for, and the company settled for over $500 million in 2007.
- Geodon (ziprasidone), Bextra (valdecoxib), Lyrica (pregabalin), Zyvox (linezolid): Pfizer paid out over $2 billion in both criminal fines and settlements with the government over false advertising and off-label promotion of uses for these drugs.
- Zyprexa (olanzapine): An antipsychotic drug marketed by Eli Lilly was hit with both criminal fines and government settlements due to accusations of false advertisement and off-label uses to the tune of a $1.4 billion settlement.
- Risperdal (risperidone), Invega (paliperidone), Nesiritide (natrecor): In one of the biggest fraud settlements in healthcare, Johnson & Johnson paid out over $2 billion in 2013 in penalties and settlements for false advertisement over use of these drugs. Resperidal, for example, was advertised to treat dementia when it was only approved to treat schizophrenia.
- Avandia (rosiglitazone), Paxil (paroxetine), Wellbutrin (bupropion): In 2012, GlaxoSmithKline paid out the largest fraud settlement in healthcare and the largest payout by a drug company for both criminal and civil liability penalties ($3 billion) to date over false marketing, failure to accurately report safety data, and fraudulent price reporting in regard to these drugs and a few others.
- Celebrex (celecoxib): Pfizer was accused of hiding safety risks associated with both Celebrex (an NSIAD for arthritis pain) and Bextra from its shareholders and agreed to pay out a $486 million settlement in 2016.
Big Pharma’s Role in the Opioid Epidemic
Pharmaceutical companies have faced many charges of fraudulent business practices, downplaying side effects of drugs, promotion of unapproved uses, rushing drugs to market without adequate testing, and other practices to try and raise profits. Perhaps one of the biggest failures of Big Pharma is their involvement in the opioid epidemic.
For many years, opioid derivative drugs like Vicodin (hydrocodone/acetaminophen) and Percocet (oxycodone/acetaminophen) were prescribed sparingly and mostly in hospital settings, as medical providers understood them to be highly addictive. The 1990s brought about a change with researchers and doctors beginning to believe the health benefits of narcotic opioids may outweigh the risks, and they began to use these drugs more often to treat chronic pain and terminal illnesses.
OxyContin and the Opioid Epidemic
OxyContin (oxycodone) entered the drug market in 1996. Purdue Pharma aggressively marketed OxyContin, pouring hundreds of millions of dollars into promoting the long-lasting opioid drug. It quickly became a billion-dollar product and accounted for 30 percent of the painkiller market within a decade of its release.
Purdue Pharma and OxyContin are not off the hook today. In January 2017, the City of Everett, Washington, hit the company with an unprecedented lawsuit. The suit claims that Purdue Pharma knowingly sold OxyContin to “shady” clinics and medical practices often termed “pill mills,” which are basically glorified drug rings. The company may have had knowledge that the drug was being illegally diverted into the black market and did nothing to stop it or notify the proper officials that this was happening. The federal government has yet to charge Purdue Pharma for its sales practices of OxyContin, but city officials in Everett are seeking tens of millions of dollars in retribution.
Rampant opioid misuse, overdose, and high rates of addiction have swept America in recent years. Today, over 2 million Americans struggle with addiction to prescription opioid drugs. Over 100 people in the United States die every day as the result of an opioid overdose.
Addiction Medication and Attempts to Stem the Tide
In 2010, in an effort to quell the growing abuse epidemic and scandal surrounding OxyContin and its diversion and abuse, Purdue Pharma rereleased OxyContin in an “abuse-deterrent” form that turns to mush when crushed. This makes it harder to snort, smoke, or inject the drug – popular methods of misuse that bypass the time-release format for a powerful and nearly instant “high.”
While diversion and misuse of OxyContin did drop as a result, many people battling opioid addiction merely switched to a cheaper and more accessible opioid drug: heroin. Heroin abuse continues to rise in the United States across most demographics, and overdose deaths almost quadrupled from 2002 to 2013.
In an effort to mitigate the damage wrought by the opioid epidemic, pharmaceutical companies have invested in new medications to help people struggling with substance use disorders.
Treatments for Alcohol Addiction
Disulfiram (Antabuse) works as an aversion therapy. This means that it effectively blocks receptors in the brain from receiving alcohol, thus counteracting any positive effects and making drinking less desirable.
Naltrexone was synthesized in the 1960s and in 1984, it was FDA-approved to treat opioid addiction. Naltrexone is an opioid antagonist that blocks opioid receptors from receiving drugs like heroin, oxycodone, and morphine. In 1994, DuPont rebranded naltrexone to ReVia, and it was approved to treat alcohol dependence and addiction.
Acamprosate was FDA-approved in the United States in 2004 under the name of Campral. It helps to mitigate alcohol withdrawal side effects and thus curb cravings to drink.
Acamprosate, disulfiram, and naltrexone are all approved and widely used to treat alcohol dependence in the United States today.
Cigarette Smoking Cessation Aids
Cigarette smoking has long been a public health epidemic. Prior to the 1990s, nicotine replacement therapy was the only viable answer for medically helping people to quit smoking.
In 1997, bupropion, an antidepressant drug, was approved to treat nicotine dependence, as it was recognized to have anti-smoking properties. In 2006, the novel medication varenicline (Chantix) was approved as a new drug for smoking cessation, as it likely has both agonist and antagonist effects. While they work differently in the brain, today, both bupropion and varenicline are FDA-approved medications for smoking cessation.
Opioid Addiction Medications
In 1972, methadone was FDA-approved for the treatment of opioid addiction. It serves as a weak analgesic and long-acting opioid that continues to fill opioid receptors, helping to diffuse withdrawal symptoms and cravings. It is still an opioid drug, however, and therefore has some potential for misuse itself.
In 2002, the novel drug buprenorphine was FDA-approved to treat opioid addiction in two forms: one containing the opioid antagonist naloxone and the other containing just the agonist buprenorphine. These medications were approved to be prescribed directly from a doctor’s office, not just from federally regulated clinics like methadone, increasing access to medical opioid addiction treatment options.
Buprenorphine is an opioid agonist like methadone, but unlike its predecessor, it has a weaker agonist effect, and after a certain amount is in the bloodstream, the effects plateau. The addition of the antagonist naloxone acts as an abuse-deterrent. Buprenorphine on its own is available in generic form. In 2016, the first buprenorphine implant was FDA-approved for opioid dependence maintenance treatmen — Probuphine.
Bunavail and Suboxone are all buprenorphine/naloxone combination products used to treat opioid addiction and maintain abstinence.
Ongoing Work in the Pharmaceutical Industry
The pharmaceutical industry is a behemoth in business and profits around the globe. As a multibillion dollar industry, it is no surprise that Big Pharma will undergo large measures to increase revenues. That being said, these companies are working to improve healthcare practices and medical interventions and to turn the table on the chronic and relapsing disease of addiction. New treatments and methods are constantly being researched, tested, and put into practice.