EXECUTIVE                                  SUMMARY                          Executive Summary • Drug CocktailsWE PRESENT T...
(4) Any investigational drug, device, or biological product packaged               separately that according to its propos...
This freedom allows physicians to concoct their own cocktails of therapies, which isever-present in the field of cancer. I...
then work a cocktail, than test the cocktail originally. This is evident in the case ofFUS1/p53 dual gene therapy and MD A...
while inhibiting too much beta-secretase impairs nerve function and causesschizophrenia-like symptoms in mice.        In a...
RECOMMENDATIONS       A. Break the FDA Approval Codes into three different approval types to ensure          hundreds of m...
should be mandated to cover at least a small portion of it (if it is granted under      Type B).              SUMMARY: Thi...
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Executive summary drug cocktails

  2. 2. EXECUTIVE SUMMARY Executive Summary • Drug CocktailsWE PRESENT THE NARRATIVE of this report and the recommendations which flowfrom it to the United States Congress, the President of the United States, applicableagencies, and the American public for their consideration. This report is the product ofnumerous discussions with statisticians, economists, researchers, physicians, patients,regulatory officials and the general public. In our country’s effort to improve the quality of healthcare, most especially indefeating dynamic and debilitating conditions like cancer, ALS, and Alzheimer’s, it isimperative that we recognize the benefits of combination therapies (i.e., drug cocktails)and create statutory incentives to stimulate the development of such combinationalproducts. These cocktails are likely to result in lower side effects and greater effectivenesswhen compared to conventional therapies, as they can attack multiple different sites ofthe same cellular-signaling cascade and multiple different molecular problems unique todiseased/infected cells, at one time, leading to lower dosages needed for each molecularmechanism to get the same or greater of an effect on the aggregate (survival or diseaseresponse). With this in mind, it is paramount to medical progress that we stimulate theamount of drug cocktails investigated.BACKGROUNDWhat are Combination Products A combinational product, as defined by 21 CFR 3.2(e), refers to the combinationof two or more separate components—be it drugs, devices, or biological products (asubstance derived from a living organism)—for the purposes of obtaining a primaryendpoint. The specific definition for a combination product is as follows: (1) A product comprised of two or more regulated components that are physically, chemically, or otherwise combined or mixed to produce a single entity; (2) Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products, and (3) A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or 2
  3. 3. (4) Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect. Once a combination product is developed, sponsors submit a Request forDesignation where the Food and Drug Administration (“FDA”) then decides whichdepartment has oversight over that therapy. This decision of department designation isbased off the primary mode of action (PMOA) of the therapy, which is determined by analgorithm if one is not able to determine, arbitrarily, which component is the primaryagent of action of the therapy.BENEFITS FROM COMBINATIONAL PRODUCTSCombination therapies (i.e., drug cocktails):1. Reduce the probability a condition, infection, or disease develops resistance to the therapy administered, as multiple active modes of action target a particular disease or infection at the same time. Thus, even if a disease/infection becomes resistant to one mechanism of action, the other agent still combats the disease or infection.2. Often result in more effectively combating an ailment when compared with administering components individually with the same dose. With many diseases and conditions the result of multiple molecular dysfunctions and infections having multiple routes to attack, combination therapies often result in an increased effectiveness against such ailments. This is because combination therapies often attack a single disease at multiple molecular points at a time. Secondly, there is the concept of drug synergy. Drug synergy refers to when the benefit of a combination therapy is greater than the sum of the effects of each therapy when administered individually. This occurs when the components which make up a drug cocktail are partially dependent on each other’s action.3. Often decrease the amount of side effects incurred, when compared with each therapy given individually at their maximum tolerable dose (“MTD”), by administering the combination of multiple independent components at lower doses than would otherwise be administered. However, there is the risk components will not be independent and will result in greater than expected side effects. This risk often deters therapy sponsors from investigating drug cocktails, as one severe side effect from the combination of two or more components can result in the discontinuation of an experimental trial.WHEN AND HOW COMBINATION PRODUCTS ARE DEVELOPED ISIMPORTANT 1. Combining already approved therapies through off-label prescription / physician created cocktails Currently, the FDA provides no oversight over off-label prescription. Once atherapy is approved for use, it can be prescribed for any indication and at any dosage. 3
  4. 4. This freedom allows physicians to concoct their own cocktails of therapies, which isever-present in the field of cancer. It is estimated that 60% of oncologists prescribetherapies on an off-label basis. The reason for this is because cancer is a disease ofmultiple molecular dysfunctions at the root of cell-growth. Recognizing multiple meansof combating this disease, physicians often prescribe multiple drugs for cancer patients ata time. The downside to this off-label prescription is these cocktail therapies were nottested in concert for safety and efficacy. This means the dosage and cocktail prescribedmay easily result in deleterious side effects. As well, physicians are not trained to maketheir own dosage recommendations, thus discovering the right dose for each individualcomponent and patient is a challenge in itself. 2. Development of a drug cocktail by combining already approved therapies with investigational or other already approved treatments Many sponsors know certain combinations may be best to treat a certain illness,yet they will still investigate components separately first to gain marketing exclusivity foreach individual component. This leads to a prolonged time for society to realize the fullbenefits of combination therapies, which in the case of seriously compromising illnessesmeans countless lives lost.Examples follow: Atripla refers to a drug cocktail which combined and tested three alreadyapproved therapies for HIV. This therapy combination of antiretroviral componentsseverely impedes the progression of HIV by attacking it at multiple points in its life-cycle. Many chemotherapy combinations for cancer are also developed by performingclinical trials with an already approved chemotherapeutic agent along with aninvestigational new agent. 3. Many components of cocktails are investigated individually first by therapy sponsors, despite obvious preclinical data and benefits supporting greater effectiveness and specificity when such components are administered in concert. There are multiple components in combination therapies that must each beisolated and proven to contribute to the overall benefit of the therapy. Safety is anadditional concern because, as these therapies are more potent, they are also more likelyto have adverse side effects. This is why the dosage of cocktails is often 10% less thanthe dosage would be if each therapy was approved for use individually. The key benefitof cocktails is the ability to specifically target a disease, infection, or condition, withmany small targets each hitting that one disease/infection site. In turn, this realizes agrand, gestalt effect on defeating many diseases and infections. However, with this specificity also comes with the less desired goal of a smallersales market for pharmaceuticals and therapy sponsors to extract profits; thereby, creatinga disincentive to produce such a cocktail unless the sponsor knows it will still reach a bigenough population. This does not appear to be the case in most instances, as sponsorscontinually show they would rather test a therapy separately, have it be approved, and 4
  5. 5. then work a cocktail, than test the cocktail originally. This is evident in the case ofFUS1/p53 dual gene therapy and MD Anderson’s choice to test each therapy individuallyrather than in concert despite obvious synergistic effects in mice. It has been well documented that a therapy sponsor’s goal is to extract the mostprofits possible, while providing small changes to already approved therapies to gainadditional patent protections. Over three-quarters of all drugs approved by the FDA arenew combinations or formulations of therapies rather than new chemical entities. Thismeans that after a therapy is developed, sponsors try to add to it rather than discoveringnovel treatments. In an effort to secure market exclusivity, sponsors will not develop cocktails untilthey have the patents on each component or such components are already approved. Thereason is because the investigation of two unproven and untested components is viewedas too risky with regards to unforeseen severe side effects, and sponsors would rathersecure each individual patent separately before investigating a cocktail to realize broadermarket bases for each. If a therapy is already developed and approved, a sponsor already has themarketing exclusivity for that market; thus, additional cocktails are tested after thesepharmaceuticals have a lock on this market. The reason a sponsor would rather have thisthan a combination therapy approved is because a single active agent is potentiallybeneficial for multiple ailments rather than just a few. The more specific the therapy (themore active components), the less is a sponsor’s market base. 4. Cases where all components of a cocktail are investigational No examples of drug cocktails were found in which all components were newchemical entities. The reason for this is likely because sponsors would rather gainmarketing exclusivity for each individual component to realize a greater market-base,before undertaking the more risky cocktail, which has a more slim market.EXAMPLES OF THE BENEFITS OF COMBINATION PRODUCTSHIV Drug cocktails are most commonly known in the field of HIV, with many patientsafflicted taking a treatment cocktail of three to four antiretroviral therapies. This uniquecombination of active components, working in concert, has the effect of drasticallyreducing HIV life-cycle by impinging on different points in this life-cycle. Thesecocktails can be taken as four separate pills which must be monitored distinctly, ortogether in the form of one pill and one dosage. As the human body does not havebeneficial viruses, these have very few side effects.Alzheimer’s Alzheimer’s is thought to be caused by the accumulation of amyloid-beta plaquein brain cells. However, studies show this toxic protein is reduced when either ofenzymes beta-secretase or gamma-secretase are inhibited. It has also been discoveredthat overly inhibiting these enzymes produce dangerous side effects – inhibiting too muchgamma-secretase leads to developmental defects, skin tumors, and a shortened life span; 5
  6. 6. while inhibiting too much beta-secretase impairs nerve function and causesschizophrenia-like symptoms in mice. In a recent study, published in Science Translational Medicine, aged Alzheimer’s-like mice were given a cocktail of inhibitors that moderately inhibited both beta-secretaseand gamma-secretase. This reduced the production of amyloid-beta plaque, withoutadverse side effects.CancerEffectiveness It is said the reason there is no cure for cancer is because cancer is not onedisease, but multiple diseases. What physicians and researchers mean by this is the factthat cancer is simply the uncontrolled overgrowth of any cell in your body, but the causeof this uncontrolled overgrowth is rooted in multiple different molecular dysfunctions inthe same cell. Moreover, when a cancer cell divides, those newly formed cells havedifferent mutations than the previous. This creates an environment where there aremultiple different types of cancer in the same very patient. To effectively combat thisailment, it is hypothesized by many physicians and researchers that drug cocktails andvaccines are adept to this challenge via their special ability to target specific moleculeswithin a cell.Targeting potent therapies to avoid toxic side effects Combining plasmodium (bacterial) proteins specific for liver cells withchemotherapeutic agent doxorubicin, researchers at the University of California, Irvineare able to specifically target liver cells with this combination therapy, effectivelyminimizing side effects felt by the heart and other organs that were previously affected.Therapies that work on their molecular target, and are safe, but not approved bythe FDA Often times when individual therapies are not beneficial in combating illnesses,infections, and diseases, combination products will realize desired effects. Hence, thereis the importance for therapies which effectively accomplish their molecular object (i.e.,inhibit molecule A), and are safe, to be approved for licensing for development aspotential combination therapies. Many therapies do not meet the FDA’s statistical cutoff for efficacy on primaryendpoints, but still provide valuable benefits to patients with little to no side effects. Thetherapies I speak of are those that provide a three month benefit to cancer patients insteadof four. While it is not clear if these therapies provide benefit to patients better thanchance would (which is the purpose of statistical testing), many of them do perform theirfunction (inhibit telomerase or a specific kinase) at a statistically significant level. Thismeans that they do what they’re supposed to at a significant level, but the level of benefitto patients’ survival rate or disease progression isn’t as grand as what is necessary to get atherapy approved. It is proposed that these therapies should be allowed for marketing orlicensing under a separate approval type. The reason for this is because these therapiesare ideal for adjuvant therapies or cocktails (therapies that do not yield adverse effects,but still perform their molecular purpose to a statistically significant level). 6
  7. 7. RECOMMENDATIONS A. Break the FDA Approval Codes into three different approval types to ensure hundreds of millions of dollars are not wasted developing therapies that are potentially beneficial for combination therapies (but which do NOT produce statistically significant effectiveness alone): i. Approval type A-1: Marketing approval to the public of a therapy, with the indication of a particular molecular or genetic characteristic and disease type, is granted if a therapy yields statistically significant results for that disease (in primary endpoints like survival rate or disease progression), shows the expected molecular response in patients, and shows safety. A brief example of how this would work is: one would take a stratified random sample of people with a given disease, stratify them into genetic / molecular characteristics; stratify those groups into disease stage; randomly allocate these groups into treatment and control groups, and test for results.ii. Approval type A-2 (similar to Accelerated Approval based on surrogate endpoints): Marketing approval of a therapy to licensed physicians and physician groups, with the indication of a molecular or genetic characteristic and a particular disease, is granted if a therapy yields a statistically significant molecular response (also known as, “biological effect”) (i.e., Tarceva shows inhibition of a cell’s EGFR tyrosine kinase) and shows safety, but does not yield statistically significant results with regards to primary endpoints like disease progression / survival rate. A pharmaceutical does not apply for this but can receive approval under type A-2 if it meets what is described above after applying for approval type A-1 or through approval type B (described below). *The therapy does not have to result in any disease response in order to obtain “physician marketing approval.”* SUMMARY: Approval type A2 is granted for a particular molecular or genetic characteristic and disease type, as the therapy yields positive results with respect to its mechanism of action working, but not with regards to progression / disease response. These therapies are ideal candidates for drug cocktails and adjuvant therapies as they do not work by themselves but may work well if you combine them with other therapies. A rigorous demand for safety is maintained of course.iii. Approval type B (the current method of approval) without stratification of molecular or genetic characteristics. This can be a supplemental application, or granted without the need for further statistical testing, if a sponsor’s study for Approval Type A1 produces certain results. This approval type is for indications with patients with unknown molecular / genetic characteristics, with its purpose being if the patient needs a therapy but cannot afford to pay for specific testing or it is not covered by their insurance (or if a sponsor cannot afford to test via stratification of molecular/genetic traits). This approval type allows patients that do not know if they have a specific molecular trait to take a therapy and insurers 7
  8. 8. should be mandated to cover at least a small portion of it (if it is granted under Type B). SUMMARY: This application allows sponsors to market their therapy and patients to obtain a therapy, with unknown molecular traits but a known disease type. This requires sponsors to run a study and perform randomized statistical tests to measure the effectiveness of a therapy in people with a particular disease type (that may or may not exhibit a molecular or genetic characteristic), or pool data from a previous study (i.e., those performed in A1 trials). B. Offer unique incentives for the investigation of combinational therapies whose components are not previously approved. (The notion behind this is to mitigate the costs pharmaceuticals face with less of a market base with such therapies.) C. Create a symposium where the FDA, pharmaceuticals, and researchers all come together to brainstorm potential drug combinations that can be made into a single therapy. Some mechanism to facilitate this interaction is gravely needed. We currently have the American Association for Cancer Research, the American Society of Clinical Oncology, and other putting on symposiums. However, we need the focus of this symposium to be brainstorming the creation of drug cocktails that can more effectively combat illnesses rather than sharing information and giving presentations on the latest research or clinical results.CONCLUSION By combining small modes of action to target an ailment at the same time, it hasbeen proven that side effects can be minimized and effectiveness maximized. As seen,there are many ways to develop such combinational therapies – physicians can develop acocktail from already approved therapies, sponsors can investigate novel cocktails fromalready approved therapies, sponsors can investigate novel cocktails by combininginvestigational therapies with already approved therapies, or sponsors can investigatecombination therapies consistent of completely new active components. We have alsoseen that it is crucial to the benefit of society at large, if a firm knows a cocktail to bemore beneficial than treatment by individual components, that firms investigate thatcocktail first and foremost. Society cannot have companies developing therapiesindividually despite knowing there are better benefits to be developed, just so thatcompany can have patent protections for a larger market. Given this, and the notion individual therapies in investigation which do not yieldstatistically significant marks with regards to primary endpoints like survival and diseaseregression, but are safe and effective in their target action, it is imperative we rewrite theapproval codes to be consistent with such knowledge. And, while we are naturally averseto change, it is for the benefits of society at large that we must create incentives andregulatory changes to realize the benefits of combination products. We look forward to a comprehensive discussion on the merits of what we haverecommended, and we will participate vigorously in this discussion. 8