Launching New Addiction Treatment Drugs

Millions of Americans are addicted to alcohol, illicit and street drugs, and prescription drugs used for nonmedical purposes.

The National Institute on Drug Abuse (NIDA) places a high priority on and funds considerable research dollars into the development of new addiction treatment drugs.

Why, then, are there only a handful of drugs approved by the Food and Drug Administration (FDA) for the treatment of addition? What’s going on here? There seems to be some disconnect between the obvious need and getting the product out in the market. In the larger sense, what does it really take to bring new treatment drugs to market?

Any discussion of developing new addiction treatment drugs has to take into account several factors. The following are factors that pharmaceutical companies look at prior to making any determination to pursue the complex and difficult process of bringing an addiction treatment drug to market.

• Who’s going to buy it? — First of all, there has to be a market for it. These are the numbers of potential customers, without which there is no incentive for pharmaceutical companies to get involved.
• Importance — There’s also the stature of the drug for the pharmaceutical company. According to many addiction treatment professionals and researchers in the field, most drug companies don’t want to be associated with drugs used for the treatment of addiction. There’s a stigma attached to addiction that lingers today. The pharmaceuticals would much rather spend their time and money on the development of a more palatable — and profitable — drug for control of cholesterol, diabetes, or a cure for cancer or Alzheimer’s disease. These are “safe” drugs, in the sense that there’s a huge market for them and there’s no stigma attached either to the patient or drug developer. Anecdotally, the pharmaceuticals place a higher importance on these high-profit, high-volume safe drugs rather than drugs for addiction treatment.
• Money — In order for a drug company to get involved with the development of a new drug for the prevention, treatment or cure of an addiction, executives need to determine how much money they’ll need to allocate for research and development (R&D) as well as the cost of doing clinical trials. This can run into the hundreds of millions, and has to include the cost of failed drugs.
• Time — New drugs have to go through a long and very involved process of FDA-required clinical testing before final approval — if they are ever approved. Countless drugs fail to meet FDA’s strict requirements, or the pharmaceutical company may run out of money for additional trials, or there may be negative side-effects, or any number of other setbacks along the way. There’s no getting around it, however. Drug development to market can take up to 14 years. There are so-called “fast-track” new drugs, which may come to market — assuming they pass all the mandated FDA phases of testing — in 5-7 years. But there’s never any assurance of success, only that there will be many ups and downs during drug development and testing phases. Drugs that seem to be highly effective may run into a snag when the FDA requires additional testing or new formulations. Pharmaceutical companies have to weigh and balance the cost of the drug development, the time before it comes to market (if ever), and the ultimate return on investment in the form of profits from the intended audience — patients.
• Likelihood of success — While it would be great if there was a crystal ball that drug company executives could look into to see if their product would be the one that succeeds and results in billions in profits, there isn’t any such predictor. Instead, executives need to go on the basis of probability studies and in-house R&D or building upon the success of another drug that may already be approved for another medical or psychological condition that may show potential as a treatment for addiction. No pharmaceutical is going to throw millions of dollars after a drug with no potential and no (or slim) chance of success.

How the process works

The drug development and approval process, as previously stated, is a complex one that usually takes many years and involves passing many hurdles before FDA approval is granted. The following information is an overview of the process, involving Preclinical, Clinical, Approval and Market, and various Phases (I through IV).

• Preclinical — Drug companies are constantly on the lookout for therapeutic compounds among the thousands that they continuously analyze. During preclinical testing, which may last from 1-7 years, pharmaceutical companies complete synthesis and purification of the drug and conduct some limited animal testing. It has been estimated that of 5,000 compounds tested, approximately five will show enough promise to convince drug company executives to proceed further in the drug development process.
• Filing an IND — When a compound shows sufficient promise, the pharmaceutical company then files an application for an Investigational New Drug (IND) with the FDA. If the FDA approves the IND, as well as an Institutional Review Board (IRB), the drug manufacturer may then begin the first of three IND phases of the drug’s development. Approximately 30% of IND drugs make it to the first phase of clinical testing.
• Phase I clinical testing — Phase I of clinical testing is concerned with determining the drug’s properties and safety profile in humans. This phase is a short-term test of the drug on 20-80 healthy volunteers to determine basic pharmacological and toxicological information in humans — especially regarding safety. Typically, a drug remains in Phase I testing for 1-2 years. If, at any time, the FDA deems that the drug is unsafe, it can stop clinical testing.
• Phase II clinical testing — Phase II clinical testing involves safety, dosing, and efficacy. During this time, small-scale and longer-term efficacy trials begin with the drug administered to volunteers of the target population. For example, if the drug is intended as a new treatment drug for heroin addicts, the volunteers have to be active heroin addicts. If the drug is for treatment of poly-substance abuse (such as alcoholism and cocaine addiction), the volunteers must be diagnosed as alcoholics and cocaine addicts. Typically, this involves 100-300 patient volunteers. During the testing, dosage levels are experimented with to find optimal dosage levels, and further safety information is gathered. This includes learning about common short-term side effects and risks. Phase II can last approximately two years.At the end of Phase II clinical testing, the drug manufacturer meets with FDA officials to discuss the process of development, continued human testing, any concerns the FDA may have, and the protocols for Phase III testing. Note: During the IND phases, manufacturers may obtain an accelerated development/review of the drug. Other usages prior to approval accommodations include treatment IND (at the end of Phase III testing) and parallel tracking.
• Phase III clinical testing — This final phase of clinical testing is usually the longest (about 30 months), and is the most extensive and the most expensive. It involves safety, efficacy, and side effects. Phase III involves large-scale clinical testing (generally 1,000-3,000 patient volunteers), and can take several months to several years to completion. Scientists examine the information from the clinical studies and seek to extrapolate it to the general population. During the tightly-controlled trials, the FDA uses the information gathered to determine whether the drug satisfies its benefit-risk relationship.
• Treatment IND — If, at the end of Phase III clinical testing, the manufacturer has applied for and received a treatment IND, the drug may be made available to patients who are suffering from a serious or immediately life-threatening condition or one for which there is no available treatment. An immediately life-threatening condition is one that will result in death within a few months. Treatment IND practice was instituted at the end of the 1980s in response to the AIDS crisis.
• Parallel tracking — Initially developed to help AIDS patients, parallel tracking makes drugs showing great promise available to patients who are not able to participate in controlled clinical trials (their condition prohibits such participation).
• Filing a NDA — Upon the completion of Phase III clinical testing, the manufacturer files a New Development Application, or NDA. The NDA approval process typically takes about two years, although since the mid-1990s, this period seems to have shortened somewhat. Thus, the time to development (IND and NDA) phases are, at the minimum, a total of nine years. During the NDA phase, the FDA consults with advisory committees made up of experts in order to obtain a broader range of advice on drug safety, effectiveness, and labeling. Once the NDA review is complete, the FDA writes to the drug manufacturer to advise that the drug is either approved for marketing, is “approvable” pending minor changes, or is not approvable because of major problems. If the drug is not approved because of major problems, the drug manufacturer can amend the NDA or withdraw it, or ask for a hearing with the FDA. When the NDA is approved, the drug may be marketed with FDA regulated labeling.

As the drug is used, the FDA gathers safety information about the drug and, as adverse events (adverse effects, side effects, allergic reactions, etc.) are reported, the agency will occasionally request changes in labeling or may issue a press release of new contraindications (warnings about use or usage in combination with other drugs, etc.) that may arise. Adverse events that appear to be widespread, systematic, and serious, may prompt the FDA to withdraw the product from the market.

Phase IV — Post-market surveillance

Once a new drug clears the FDA hurdles and is approved for use in the marketplace, that’s not the end of the process. According to ClinicalTrials.gov, studies are done after the drug or treatment has been marketed to gather information on the drug’s effect in various populations and any side-effects associated with long-term use. Thus, the FDA-approved drug now in the marketplace continues to receive considerable post-market surveillance for any instances of side-effects or other negative consequences of use. This period lasts from 11-14 years.

FDA mandates increase

Over the past couple of decades, the number of FDA regulations and requirements has tended to increase — and dramatically so. In 1980, for example, the typical drug underwent 30 clinical trials involving approximately 1,500 patients. By the mid-1990s, the typical drug underwent 60 clinical trials involving approximately 5,000 patients.

Why the increase in clinical trials and patients? Despite extensive testing, safety and efficacy trials, the outcome of any new drug is uncertain. In essence, the FDA never knows whether the new drug, device, use, or claims will be a net good or a net bad for society. The FDA seeks to avoid errors. There are two types of FDA errors: Type 1 and Type 2.

• Type 1 error — Type 1 errors occur when the FDA releases a drug that turns out to be a net bad for society. These errors produce identifiable victims and are the subject of intense media publicity, public concern, and congressional action against the FDA. Obviously, the FDA takes great pains to avoid Type 1 errors by increasing the length of time for the drug approval process and by requiring more extensive clinical trials. This caution, however, often proves counter-productive and results in many more Type 2 errors.
• Type 2 error — Type 2 errors occur when the FDA rejects a new drug, device, use or claim that would be a net good for society. These Type 2 errors are less visible because doctors, patients, and journalists are usually not aware that a potential new drug has either been delayed or suppressed and that it would have resulted in good for society — in other words, it would have saved the lives of patients. Critics of the FDA’s stringent requirements point to the numbers of victims of Type 2 errors who die because the FDA rejected potentially life-saving drugs.

The FDA exerts considerable control over all three phases of the clinical trial process. At any stage, it can and often does request additional clinical trials as well as changes in trial protocols.

Length of time to market

A 2003 study by DiMasi, Hansen and Grabowksi of the Tufts Center for the Study of Drug Development (CSDD) estimated the time to bring a new drug from the start of clinical testing to marketing approval at approximately 90.3 months — or 7.5 years. This is in addition to any development time which occurs before clinical trials.

Estimated costs

Including the expense of failed drugs, DiMasi, Hansen and Grabowski estimated it costs $802 million to take a drug from Phase I testing to approval. The authors found that 50% of this figure is the cost of capital needed to finance R&D over the period.

According to PhRMA (the Pharmaceutical Research and Manufacturers of America), U.S. drug companies spent $39.4 billion on R&D in 2005. Most of the money goes to the clinical trials necessary for FDA approval of a drug.

Funding for clinical research trials

Funding for clinical research trials comes from a number of sources. These include the National Institutes of Health (NIH), the National Institute on Drug Abuse (NIDA), the Department of Defense (DOD), the Department of Veterans Affairs (VA), and private industry, such as biotech companies, pharmaceuticals, foundations, and medical institutions.

New industry emerges for clinical trials

With so much time, effort and money invested in the development of new treatment drugs, it’s no wonder that pharmaceutical companies are spending considerable additional time and money during the Phase IV post-market period. Some say this is the fastest-growing area of clinical research today. In 2007, industry investment in post-marketing research was estimated to top $12 billion.

Post-marketing research enables pharmaceutical companies to expand existing markets, enter new markets, create and deliver messages comparing their products to the competition, and secure a niche in the crowded marketplace with their products.

Industry executives gather benchmark data and best practice information to enable them to make key strategic and operational decisions in Phase IV research. These center on trial management structure and oversight, research strategy, study design and execution, study timelines and cycle times, performance metrics and management, operational activities, trial budgeting and outsourcing, and trial staffing.

Participating in clinical trials

Information on clinical trials for addiction treatment drugs is available by going to ClinicalTrials.gov. This is a registry of federally and privately-supported clinical trials conducted in the U.S. and around the world. Addiction treatment professionals and persons interested in volunteering to participate in the trials can obtain the necessary information, including requirements, status of recruitment for the trials, when and where the trials will begin, information about the duration of the trial, and other information.