Federal Drug Administration and the Approval Process for Antidepressants - Term Paper Example

Federal Drug Administration and the Approval Process For Antidepressants: The Need for Process Changes or Brief History of Antidepressant Development Monoamine Oxidase Inhibitors (MAOIs) - Antidepressant pharmacotherapy began in the 1950s with the development of monoamine oxidase inhibitors (MAOI), imipramine and iproniazid. Up until this point, treatments for depression and mood disorders ranged from biological applications such as insulin coma and electric shock therapy, or in other cases, chemical treatments using succinic and/or malonic dinitrite, lactic acid (López-Muñoz, Alamo, Juckel, & Assion, 2007). In the early part of the 20th century, chloral hydrate, barbiturates, amphetamines, and opium derivatives were also used, with none of these applications showing effective outcomes at satisfactory levels. The fields of psychopharmacology and psychiatry joined together in developing those first groups of psychoactive drugs in the discovery of imipramine and iproniazid, lithium (1949), chlorpromazine (1952), meprobamate ((1954), and chlordiazepoxide (1960). As often happens in scientific research, the basis for much of these discoveries was part of early research during the late 1800s into the early 1900s when working on the chemistry of sugars. This early research was later rediscovered in the 1950s while working to solve issues with tuberculosis. With the early research’s compounds resynthesized for the issue of tuberculosis through isoniazid, it also accidently provided the foundation for the future of developments in antidepressant pharmacotherapy, first of monoamine oxidase (MAO), then MAOI, using iproniazid (López-Muñoz et al., 2007). The use of iproniazid showed a much greater power than isoniazid in tuberculosis patients, stimulating the central nervous system to the point that patients acquired greater vitality and were ready to leave the hospital and to socialize more. This lead to a rethinking of using iproniazid for psychiatric patients and, in research, improvement was noticed with depression patients gaining back weight, a higher level of activity and improved sleep levels. The drug was marketed as marsilid, but was better known as a solution for tuberculosis. Other drugs were soon developed, such as tranylcypromine, isocarboxazid and phenelzine among others. Over the years these were being prescribed, there were some side effects such as some patients who ate cheese with tyramine as an ingredient, had reactions called the “cheese effect” (López-Muñoz et al., 2007). Tyramine was also found in in wines, smoked or pickled meats, caffeinated drinks, chocolate, and other foods (Wrobel, 2007). Other patients suffered from headaches and, occasionally, subarachnoid intracranial hemorrhages. Yet, since more advanced research and development has continued through the decades, MAOIs are still considered a good backup for those patients who do not respond to more commonly prescribed drugs. Tricyclic Antidepressants (TCAs) - The first TCAs to be developed was based on research with Thorazine and imipramine, a class of antihistamine. These were based on previous studies with allergies and antihistamines that also showed an efficient level of sedation during surgery, a far better outcome than in using ether or chloroform. Chlorpromazine in Europe (Thorazine in the U.S.) was such an early drug which was used for those highly psychotically agitated patients and showed to be very effective in calming patients down. Thorazine, in many cases, allowed many patients who had been deluded and hallucinating for quite some time, to recover from their psychoses and begin to lead normal lives again (Wrobel, 2007). Many of these drugs had their origins in industrial chemistry, particularly during World War II, but were later moved to pharmaceutical departments of civilian chemical companies, such as Hoffman-La Roche in New Jersey. Imipramine was the first true generation of TCAs distributed by Ciby-Geigy and was better known in the United States as Tofranil. Elavil (amitriptyline) was another that followed after Tofranil. These drugs were called tricyclic because the drug’s molecular structure had three rings of atoms (Wrobel, 2007). However, both the MAOIs and the TCAs sometimes had unwanted effects in that some of the chemical changes in the brain would be fixed, other changes also occurred, causing severe problems. Thus, it was determined that these drugs were indiscriminate in how the chemical flux of the brain was altered. For those who already had a high risk of suicide and/or were alcoholics, prescribing these drugs could be very dangerous, even fatal. Selective Serotonin Reuptake Inhibitors (SSRIs) - Prozac, also known as fluoxetine in its generic form, is one of the most well-known SSRIs, making its first appearance in the market place around 1988 (Wrobel, 2007). It was designed specifically as a mood enhancer to work with brain neurotransmitters in the alleviation of serotonin shortages in nerve cells so that there was more for the brain to use as needed. Early research showed in evaluating serotonin levels in the brains of those who had died from suicide, it was noted that there was far less serotonin in their brains than those who had died by an accident or heart attacks (Wrobel, 2007). The study of how different drugs, including cocaine in research, affected the relationships with norepinephrine and the other neurotransmitters, which then affected mood behavior, provided the foundation for development of the SSRI drugs most commonly used today. Additional advances have also been made by combining the analysis of molecular compound structures with nuclear magnetic resonance imaging to view how the changes are occurring during biological activity. This provided ways to test whether the right neurotransmitter was being acted upon during research (Wrobel, 2007). As more medical advances are being made, new drugs will continue to be developed to fight the war on depression and other related issues. The FDA and the Approval Process for Antidepressants and Need for Updates from 1977 In 1977, the United States Food and Drug Administration (FDA) created a set of guidelines for standardizing the study and research conducted with antidepressants in order to seek approval for distribution on the open marketplace. Since 1977, however, medical advances, technology, and study design now show that these guidelines should be updated in order to provide a more efficient and rigorous path, from designing the studies, the testing process, and the approval process (Hanrahan, 2014). The branch of the FDA responsible for overseeing the review and approval of prescription drugs is the Center for Evaluation and Research (CDER). Clinical evaluations are conducted in phases (I, II, III, and IV) after the creation first of the new molecular entity (NME) and then the investigational new drug (IND) application. After the initial applications comes the controlled clinical trials which are outlined by a study rationale, objectives, selection criteria, sample size and methods of analysis. There will also be a control group and/or dose-comparison group(s), with testing done over a period of time, with the findings presented after each study in the different phases (Hanrahan, 2014). There are several issues with the guidelines as they stand today. Hanrahan (2014) notes that studies in phases II and III provides only a broad recommendation of how much time should be used for these studies, from only days to several weeks. Hanrahan (2014) also points out that researchers can only use evaluation scales currently used in the medical community at large for a number of other issues, rather than one which is dedicated to this specific research. Accordingly, the use of rating scales to show improvement and benefits are not always consistent between studies. Finally, as depression therapy is now mostly involved with SSRIs, the current treatment comparators are only using outdated ones for TCAs and MAOIs, and the diagnosis of depression can only be based on the Diagnostic and Statistical Manual of Mental Disease. FDA Clinical Evaluation Phases Phase I: After the NME is designed and the IND application is made, Phase I begins, with the objective as determining the human tolerance within pharmacokinetic parameters concerning absorption, distribution, determining metabolism and excretion of the drug. The subjects are healthy volunteers over the age of 21 who do not take any other drugs, but excluding women capable of childbearing, children, and patients with serious diseases (Hanrahan, 2014). The trial setting is in a confined area where close supervision is maintained on a 24-hour basis while treatment is given. The study design can be presented in several ways: as a single or multiple dose escalation method, or double-blind, parallel group with a placebo control (Hanrahan, 2014). The sample size can be a variable amount, with as small as six subjects, but usually 20 to 80 subjects (FDA, 2014a), and can last for several days to several weeks. Assessments in this phase are on a continuous basis through complete physical examinations, with vital signs, liver, renal and cardiovascular laboratory tests, and any other tests required, based on the drugs being used. Dosage amounts are at the minimal level, usually one-fifth the nontoxic maximum amount used in previous animal tests (Hanrahan, 2014). As noted, voluntary subjects are healthy and the objective is to analyze how the drug is metabolized and excreted in the healthy group before moving on to those tested in the next phases who have the diagnosis for which the drug was created (FDA, 2014a). If there are events of toxicity and severe enough reactions in this healthy group, then the drug does not proceed to the next phase, but must be reworked again. Phase II: In this phase, based on initial outcomes of Phase I testing, the second phase’s objective is to identify efficient responsive therapeutic conditions by estimating the appropriate clinical dosage, the suitable duration for treatment, and to also determine if there are any adverse effects caused by the drug. The subjects in the first part of Phase II, should be similar to those in Phase I, while in the later part of Phase II, the subjects may be split out into more homogenous groups by age, gender, weight and setting. In this later part, the subjects may also present a depressed mood, with other associated symptoms (Hanrahan, 2014). As in Phase I, the early part of Phase II will be in an inpatient setting for close monitoring, while in the later part of the phase, the subjects may be outpatients but continue to be closely monitored in various ways, depending on the drug. The study design in the early phase can be uncontrolled, but in the later section, these should be conducted with a matching placebo or an active control group. Parallel and cross-over designs may be used as well. In both Phase I and II, all participants must undergo a washout period which is a cleansing of the body of any other drugs. The duration of the phase studies are from days to weeks, with one or more studies conducted over six weeks or more. The sample amount can be variable in the early part of the phase but should have at least 20 or more patients within each treatment group in the later part of Phase II (Hanrahan, 2014). In the open trials, the dosage can be increased until a good therapeutic response is achieved. In the later part, with double-blind, controlled studies, the dosages are fixed, with some room for adjustment if criteria allows it. Assessments in this phase, use the same extensive physical examinations as Phase I, with the addition of using global scales to describe the severity of the illness, where applicable. These scales include Raskin, Beck, Wittenborn, MMPI, Hamilton and Zung, commonly used in other drug trials. Additionally, socio-economic and clinical backgrounds are also included, along with any history of therapies previously provided. Phase III: The third phase is to confirm the findings from previous studies and the efficacy of the drug’s activities, along with any side effects for the various patient sample demographics. The population samples within each group should be similar in variables, but each study population should have some differences from the other study populations. The settings for the studies can be outpatient, inpatient, and through private practice. Of these studies, the third phrase requires that three to five studies conducted should have the new compound group balanced with a placebo or active control group for observing efficacy (Hanrahan, 2014). Data should also come from several studies, to provide a better overview, particularly in more long-term safety studies which last from three to six months. The sample for these studies requires at least 30 to 50 patients in each group (preferably several hundred to 3,000 subjects (FDA, 2014a)) within controlled trials to gain a better perspective. Similar to Phase II in open trials, dosages can either be increased until a satisfactory therapeutic response is attained, but are fixed in double-blind controlled studies, with a range allowance dependent on specific criteria (Hanrahan, 2014). The assessments are conducted in full, using the required scales, and a complete history of the patient is also provided, as regards socio-economic and clinical characteristics. In this phase, the drug is usually tested with another drug and/or a placebo, in order to measure effectiveness and trials must be exhaustive and efficient. When this phase is complete, the FDA and the drug sponsors meet to review the information and determine whether the results allow for the NDA application to be submitted for marketing. All parts of the marketing process, including what will go on the label, is reviewed by the FDA before the drug can be presented to the marketplace (FDA, 2014a). In some cases, approval for the drug and the marketplace can take a significant amount of time. Phase IV: This phase is the final part after approval is received by the FDA to market the drug within a clinical setting. Extensive records must be kept by the doctors and nurses involved in monitoring patients who have been prescribed new on-the-market drugs. Sample populations which had not been part of the studies, such as adolescents, criminal justice patients, and military personnel, must have stringent supervision to note any side effects as there is usually little to no information available. While careful records are kept by attending medical personnel, these are usually one-on-one situations, and the only way to get overviews on specific populations with similar variables is to conduct secondary research for information coming in to a centralized medical repository which might show certain side effects for a certain population sample (Harwood & Myers, 2004; FDA, 2014b). Once the drug is on the market, the FDA sets into action the Post-Approval Risk Assessment System whereby the sponsor of the drug, provides periodic safety updates and must report any side effects or other issues that may arise. The FDA MedWatch voluntary system is where doctors and other personnel, including consumers, may report problems they are having with the drug. When need-to-know risks are uncovered, then the medicine’s label and warning descriptions are updated. In severe cases, drugs have had to be pulled from the marketplace (FDA, 2014b). Pristig (Desvenlafaxine): Misuse of the 17-Item Hamilton Rating Scale for FDA Approval Desvenlafaxine succinate (DVS), known on the market as Pristig, is used for the treatment of major depressive disorder (MDD) and is classified as a dual-acting serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor (SNRI) (Lieberman & Massey, 2009: Lourenco & Kennedy, 2009). In Phase III studies, the first one used an 8-week double-blind placebo controlled trial with a sample of 480 adult patients from 25 nationwide centers, who had been diagnosed with MDD. The 17-item Hamilton Rating Scale for Depression (HAM-D17) was used throughout Phase III trials in measuring outcomes, with the Clinical Global Impressions-Improvement scale (CGI-I), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions-Severity of Illness scales (CGI-S), providing secondary efficacy measures (Lieberman & Massey, 2009). The Visual Analog Scale-Pain Intensity (VAS-PI) scale was also used (Lourenco & Kennedy, 2009). Included ratings were the rates of response (≥50% decrease of HAM-D17 from baseline), remission rates (HAMD-D17 score ≤7), and the VAS-PI overall score. In Phase III, fixed dosages were provided at baseline: 100 mg, 200 mg, or 400 mg daily, along with the placebo group for comparison (Lieberman & Massey, 2009). All studies conducted during this period were eight weeks long in duration. As previously noted earlier, while there are accepted rating scales used in drug trials, there is no specific requirement as to which one is to be used, causing something of a problem when trying to compare outcomes within secondary research for more information about studies. As an example, when DVS was being tested, using the HAM-D17, this was an upgraded version rather than the original (Hanrahan, 2014). So, while other tests may have been conducted with DVS, it is not clear which rating version was used, causing something of a problem in determining results. Accordingly, another drug being tested at the time was escitalopram, which used the Montgomery Asberg Depression Rating Scale instead. Practioners, who are trying to determine the benefits of these drugs under certain criteria, may have a hard time differentiating between drugs because of the differences in rating scales used during the studies. Studies should also be consistently conducted in the same way across groups during the phase, other than the dosage amounts, so as to be sure of proper recording in ratings. In one study of DVS during Phase III, the placebo scores were not differentiated out of the overall ratings, which led to skewed results (Lieberman & Massey, 2009). The other findings of the Phase III studies for DVS also showed that there were not always marked differences between the placebo group and the active drug groups, based on the dosage amounts. One study showed that 50 mg was just as effective as the higher active drug dosages of 100, 200 and 400 mg, and that 50 mg dosage was the minimum provided at any time during the studies. Therefore, it does indicate that further testing should be done on lesser dosages to see how low the dosage can go and still achieve efficacy (Lourenco & Kennedy, 2009). Along with this issue, is the case for placebo control, which does not appear to be an effective method for control testing. The final mention for this particular drug and the Phase III trials is that longer trials should have been used to determine just how well the drug did at the various dosages, and more importantly, how withdrawal from the drug was rated after such a longer time. Eight weeks is really not enough time to fully explore the side effects and withdrawal issues that can occur, particularly when the drug showed to cause certain side effects during use and in discontinuation. Recommendations for FDA Guideline Changes in Antidepressant Studies This paper has shown the numerous methods available for rating scales used during all FDA medical research studies, yet it is also shown that there should a narrowing of the guidelines for rating depression studies in order to fine-tune results more effectively, including determining which rating scale is the best to use consistently. There should also be more consistency between types of antidepressant drug testing, such as using the same dosage trial at least once for every Phase III conducted, and that the control group might be another antidepressant within the same family of drugs, such as MAOIs with another MAOI, a SSRI with another SSRI, and a SNRI with another SNRI. This provides a common thread for secondary research when trying to determine which drug performs better under certain criteria of a diagnosis and sample group. Obviously, when there is a new classification of drug being tested, then most likely the closest type of drug to the new one, should be the control group. In all cases, the patient or subject samples should be in a blind control test arrangement to offset any bias or influence as to the patients’ perceptions of the drug(s) being used (Kosten & Kranzler, 2004). Ten Most Recently FDA Approved Antidepressant Drugs There continue to be studies done to develop new antidepressant drugs, but research has slowed down, perhaps in light of wanting to make sure that proper testing takes place and that a new drug has been properly vetted. Such was the case with Wellbutrin XL, which was first approved by the FDA in late 2006. What turned out to be a big issue is that the FDA approved it after the sponsor conducted tests at only one level of dosage, instead of doing several studies using different dosages and, subsequently, after numerous reports of side effects, the drug was recalled (Maris, 2012). This highlights the need to do extensive and thorough testing before the drug ever makes it to market. It also brings out the fact that the FDA is not always complete in reviewing the work done in research trials for new drugs. Consequently, not as many antidepressant drugs are being produced and, certainly, not in a mass production line. Some of the latest drugs are listed below although one or two may have escaped detection for this list. Brintellix, Oleptro and Viibryd, are three of the latest output in SSRI and SNRIs for the market in 2013 (Tartakovsky, 2011). Other SSRI drugs left out are Paxil (paroxetine) because it tends to be prescribed for those who have trouble sleeping. Hopefully, new research will continue ahead to create those solutions that have suitable testing and far less negative effects than the earlier versions of antidepressants. Name Date Type or Classification Brintellix (vortioxetine) 2013 SSRI/SNRI Viibryd (vilazodone) 2011 SSRI Oleptro (trazodone XR) 2011 SARI Cymbalta (duloxetine) 2009 SSNRI Seroquel XR (quetiapine XR) 2009 SSNI Symbyax (olanzapine/fluoxetine) 2003 SSRI Abilify (aripiprazole) 2002 SSNI Lexapro (escitalopram) 2002 SSRI Celexa (citalopram) 1998 SSRI Prozac (fluoxetine) 1987 SSRI Table 1. (Tartakovsky, 2011; Phelps & Carlet, 2011) Resources FDA. (2014a). The FDA’s Drug Review Process: Ensuring Drugs are Safe and Effective. The Food and Drug Administration (FDA) Online. Retrieved from http://www.fda.gov/drugs/resourcesforyou/consumers/ucm143534.htm. FDA (2014b). Drug Approval Process. The Food and Drug Administration (FDA) Online. Retrieved from http://www.fda.gov/downloads/Drugs/ResourcesForYou/Consumers/UCM284393.pdf. 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Kirsch, I., Deacon, B.J., Huedo-Medina, T.B., Scoboria, A., Moore, T.J., & Johnson, B.T. (2008). Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PloS Med, 5(2). Retrieved from http://www.plosmedicine.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pmed.0050045&representation=PDF. Kosten, T.R., & Kranzler, H.R. (2004). What will We Learn from the FDA Clinical Trials Process and What Will We Still Want to Know About Immunotherapies and Depot Medications to Treat Drug Dependence? National Academy of Sciences. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK24637/. Lieberman, D.Z., & Massey, S.H. (2009). Desvenlafaxine in major depressive disorders: An evidence-based review of its place in therapy. Core Evidence-Dove Press Journal, 4, 67-82. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2899788/. López-Muñoz, F., Alamo, C., Juckel, G., & Assion, H.J. (2007). Half a century of antidepressant drugs: On the clinical introduction of monoamine oxidase inhibitors, tricyclics, and tetracyclics. Part I: monoamine oxidase inhibitors. Journal of Clinical Psychopharmacology, 27(6), 555-559. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/18004120. Lourenco, M.T.C., & Kennedy, S.H. (2009). Desvenlafaxine in the treatment of major depressive disorder. Neuropsychiatric Disease and Treatment, 5, 127-136. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695227/pdf/ndt-5-127.pdf. Maris, D. (2012). A Drug Recall That Should Frighten Us All About the FDA. Forbes Online. Retrieved from http://www.forbes.com/sites/davidmaris/2012/10/10/fda-recall-points-to-serious-problems-at-the-fda/. Phelps, J., & Carlat, D. (2011). Four “New” Antidepressants. Or Are They? The Carlat Report: Psychiatry Online. Retrieved from http://www.thecarlatreport.com/free_articles/four-%E2%80%9Cnew%E2%80%9D-antidepressants-or-are-they-free-article. Silberman, S. (2009). Placebos Are Getting More Effective. Drugmakers Are Desperate to Know Why. Wired Magazine Online. Retrieved from http://archive.wired.com/medtech/drugs/magazine/17-09/ff_placebo_effect?currentPage=all. Tartakovsky, M. (2011). Depression: New Medications on the Horizon. Psych Central Online. Retrieved from http://psychcentral.com/lib/depression-new-medications-on-the-horizon/0005794. Wrobel, S. (2007). Science, serotonin, and sadness: The biology of antidepressants. The FASEB Journal, 21(13), 3404-3417. Retrieved from http://www.fasebj.org/content/21/13/3404.full.pdf+html. Read More