Executive summary molecular medicine

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Executive summary of molecular medicine -- the current market, challenges, and suggestions for improvements

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Executive summary molecular medicine

  1. 1. INNOVATION AND CHOICEREPORT ON THE PROMISE OF AND IMPEDIMENTS TO MOLECULAR MEDICINE Executive Summary Innovation and Choice (202) 556-0614
  2. 2. EXECUTIVE SUMMARY Executive Summary • Molecular Medicine WE PRESENT THE NARRATIVE of this report and the recommendations whichflow from it to the United States Congress, the President of the United States, relevantagencies, and the American public for their consideration. This report is the product ofyears of discussion with statisticians, economists, researchers, physicians, patients, thegeneral public, and molecular medicine experts. The promise of molecular medicine is great. By treating patients based on themolecular attributes of their disease and unique patient molecular profiles, optimaltherapeutic choices and personalized medicine will come to fruition. However, thispromise needs not just money, but crucial infrastructural database creations to facilitatethe transfer of valuable knowledge from relevant studies. Once this infrastructure iscreated, the innovative results of research can be rapidly translated into clinical benefitsto patients. As will be illustrated, this translational of knowledge to physicians, and thuspatients, is fundamental to molecular medicine’s integration into the standard of care.CURRENT MEDICAL PRACTICEDiagnostics When you go to your doctor he or she will ask you what is bothering you, performa physical examination, as well potential imaging and laboratory tests, all in an attempt tonarrow the range of illnesses or infections which may be afflicting you. This process,known as differential diagnosis, involves first considering the most probable diagnoses,then narrowing down these diagnoses, by the aforementioned methods, until theexamining physician believes he or she has reached the correct diagnosis. A physicianwill also consider his or her past experience, and associations of various symptoms withcertain illnesses and infections, in diagnosing his/her patient. The more serious thesuspected illness or infection, the further a physician is likely to go in laboratory andconfirmatory testing to ensure he or she is precise with his/her diagnosis.Treatment After a physician deduces a likely hypothesis of the underlying cause of thesymptoms presented (‘clinical symptoms’), he or she will prescribe a treatment for thatsuspected illness. If this treatment does not work, he or she will repeat this process, or trya different dosage; thereby, gathering new information, hypothesizing a new illness toaccount for the patient’s symptoms and laboratory results, and prescribing a treatmentbased on this new hypothesis until the patient improves. This is known as thehypothetico-deductive (trial-and-error) method of treatment: “Currently, physicians prescribe medication through a trial-and-error method of matching patients with the right drugs. If the prescribed medication does not work for the patient the first time, the physician will try a different drug or dosage, 2
  3. 3. repeating the process until the patient improves.” -- American Medical Association One of the most difficult aspects of this process, for physicians, is that manypatients often display common clinical symptoms which originate from different causalmolecular pathologies (diseases). This is often due to altered genomic (gene) and/orproteomic (protein) expression levels in different subtypes of disease, leading manydoctors to believe they know what condition a patient has, prescribe a medication, and bewrong multiple times; hence, prolonging the time for patients to receive optimaltreatments – something that is crucial when dealing with serious illnesses like cancer orAlzheimer’s.Therapeutic Safety and Efficacy Pharmacological treatments (drugs), if administered orally or by any means otherthan intravenously, are broken down (metabolized) by the body into subsequentchemicals, which are then converted into other chemicals, which (hopefully) ultimatelyact solely upon the diseased cells, infectious cells, or over-expressed / under-expressedextra/intracellular molecules. How the human body absorbs, distributes, metabolizes andexcretes a drug (often referred to as ADME) is known as a therapy’s pharmacokinetics,whereas the drug’s effect on the patient’s body and infection/disease is known as atherapy’s pharmacodynamics. It is important to note many therapies have an attraction,or ‘affinity,’ for multiple molecular sites, binding and affecting multiple differentsignaling pathways within a cell and patient, post administration. This consequentialbinding to multiple molecules results in side effects which are near impossible to avoid,unless limiting the distribution of a given therapy. Also important to understand is that a therapy’s pharmacodynamics andpharmacokinetics—together called pharmacology—are different with slight genotypicand phenotypic variations within each cell and each person. This means variations ingenes and proteins expressed by each cell, in each respective person, will affect how welland if a therapy will be absorbed, distributed, metabolized or excreted from a person’sbody, as well how effective each therapy’s mechanism of action will work on eachpatient (effectiveness).Adverse Results from Trial-and-Error, One Size Fits All Treatment The ensuing results when the causes of illnesses are not known and treatments areprescribed on a trial-and-error basis -- 1. A prolonged time to receive optimal benefits to patients, costing patients time and money – which, in the case of seriously compromising illnesses, can cost a person’s life or life’s savings. 2. Unnecessary side effects: 100,000 deaths and over 2 million hospitalizations occur each year, in the United States, as a result of adverse drug reactions. 3. The development of pathogenic resistance to treatments, negating billions of dollars and decades of research in the development of each therapy. For example: • If a bacteria comes into contact but is not killed by an antibiotic, then it can become resistant to that antibiotic. It does this by changing the 3
  4. 4. structures expressed on its cell surface. As well, tumor cells can adapt to treatments that do not effectively target and kill those cells. • Ensuing Societal Problem with infectious agents/pathogens: With bacteria and viruses, these resistant strains often spread to the rest of society, thus rendering therapies completely useless. • Ensuing Societal Problem with cancer and other highly mutagenic (mutating) diseases: If enough people with a specific tumor become resistant to a medication, the therapy is rendered useless and is no longer profitable for companies; thus, will be shelved. o Once these ailments become resistant, new cellular signaling pathways must be discovered and mapped, novel therapeutic targets need to be found; and, then the whole process of drug development (i.e., preclinical/clinical investigation) must be repeated.MOLECULAR MEDICINEWhat is it? Molecular medicine refers to methods allowing physicians to diagnose and treatpatients at the molecular level. This is realized by taking a sample of cells from a patientand analyzing this sample at the genomic and proteomic level, looking at expressionlevels of, mutations to, and slight variations in genes, proteins, and various enzymesknown to be associated with certain types of diseases/infections, symptoms, andpharmacological characteristics (i.e., ADME and therapeutic effectiveness). To fully understand the benefits molecular medicine offers, it is important toremember that every process occurring in our bodies can be broken down to molecularattributes governing it – whether that is a reaction to a drug, metastasis of cancer, orresistance development to antibiotics. Hence, the importance of molecular testing is theability to isolate the underlying molecular attributes causing each person’s clinicalsymptoms (and any side effects), thereby allowing clinicians to match availabletreatments with those molecular causes, as most pharmacological agents have knownmolecular mechanisms of action. In addition to this diagnostic-therapeutic matching,molecular testing offers to many additional benefits to quality patient care.Benefits from Molecular Medicinea) Diagnostic-Therapeutic Matching (DxRx): By profiling a patient’s molecular characteristics, physicians are able to match treatments, with known molecular mechanisms of action, with patients whose diseased/infected cells exhibit those particular molecular traits thereby maximizing effectiveness. Such tests, produced concurrently with a therapy, to match diseased characteristics and molecular profiles with the known molecular actions of a therapy are known as “companion diagnostic tests.” Added Benefit to Society: o The development of drug resistance is curbed as physicians would now prescribe treatments only for those ailments for which these treatments are known to be most effective. (By testing a person’s ailment before 4
  5. 5. treatment, clinicians would be able to isolate and be sure of the molecular causes of clinical symptoms presented.)b) Minimizing Side Effects: By profiling individual patient’s molecular traits prior to a therapy’s administration, clinicians are able to minimize side effects by ensuring patients exhibit all necessary enzymes to absorb, distribute, metabolize and excrete therapies. Clinicians can also compare molecular expression profiles of normal cells with that of diseased/infected cells to avoid side effects of therapies not geared specifically toward infectious or diseased cells.c) Predisposition (PDx) Testing: By profiling the genetic characteristics of an individual (or their progeny), clinicians or genetic counselors may be able to predict the risk of that individual developing a particular illness or disease. This could lead to preventative measures, saving individuals from life-threatening illnesses and higher future medical costs.d) More Accurate Disease Detection & Patient Prognoses: By analyzing a patient’s molecular profile, clinicians can more accurately diagnose patients, thereby giving more accurate prognoses on the likely outcome and speed at which a patient’s ailment will progress.Impediments to the Full Adoption of Molecular Medicine 1. Physicians are busy and often unable to stay up-to-date with novel studies and publications. • There are studies constantly published on novel proteomic and genomic markers, with new molecular markers being found, new components in pathways being discovered, and old markers showing novel associations with other proteins and illnesses. However, in dealing with insurance forms and trying to see as many patients as possible in the day, many physicians are too busy to keep up with these relevant publications (of novel genomic / proteomic biomarkers for diseases, the metabolism of therapies, and intra/extracellular signaling), as well as the molecular tests associated with such discoveries. 2. There is a lack of adequate databases coherently illustrating gene/protein- disease associations and gene/protein-therapeutic effectiveness and safety relationships discovered and published in journals and medical texts, as well as a lack in the rapidity with which novel publications and results are updated and added to such databases. • The added lack of organized, centralized information on new studies and results further deters physicians from keeping up with the latest discoveries instrumental to providing the most effective care for patients. 3. Physicians can prescribe therapies without giving these molecular tests. • Considering many patients want a quick fix and physicians’ limited time, many physicians are content prescribing a therapy without administering molecular tests (by trial-and-error). This is most especially true if that therapy is the “standard of care,” and a 5
  6. 6. physician can avoid potential litigation without administering such a test. 4. There is the question of who develops and bears the cost for pharmacogenomic tests associated with specific therapies, known as “companion diagnostic tests,” which are currently not required in the investigation and development process of novel therapies. 5. Off-label Prescription It is understood by the National Institute of Health that an estimated 60% ofmedical professionals dealing with cancer prescribe medications on an off-label basis –meaning for an indication other than the approved and tested indication of a giventherapy. Two problems exist here – (1) patients believe these therapies are tested forsafety and effectiveness for the indication prescribed, and (2) disease resistance to thetherapy occurs if the therapy is not specific and sufficiently potent to the target disease orinfection. This issue would be slightly less important, but patients are often not informedsuch therapies are prescribed off-label. Patients have an inherent trust in their physician(and government), and, if not told otherwise, believe the therapies they are taking haveproven benefits and a lack of observed side effects. However, in the case of off-labelmedications, the therapies prescribed do not have proven benefits or a lack of observedside effects for the indication prescribed. While physicians often have valid reasons to suspect these therapies may bebeneficial for patients on an off-label basis (and, hence, prescribe them to patients), it isimportant to share with patients the knowledge these therapies which are prescribed havea lack of proven efficacy and safety for the prescribed dosage or indication.RECOMMENDATIONSGENERAL Bring together the stakeholders involved and institute a system where United States’ physicians can effectively translate the benefits of molecular diagnostics to patients through a greater understanding and utilization of validated molecular tests. This can be accomplished by (1) integrating this technology into general medical care practices, (2) facilitating the creation of effective, centralized databases to best advance from novel genomic and proteomic discoveries, (3) setting a standard protocol for the development of pharmacogenomic and companion diagnostic tests, and (4) better informing patients about off-label prescriptions.OUTLINEA. Integrate molecular diagnostic technologies with insurance and health care practitioner platforms, providing this option (and some form of coverage of this option) to patients. I. Address physicians’ lack of current knowledge in genetics and cellular signaling: (a) Suggest that physicians and/or health care provider groups hire or consult researchers or recent college graduates in molecular medicine who 6
  7. 7. understand these systems, potentially integrating these graduates into the health care practice to work side-by-side with physicians. (b) Work with continuing medical education institutions to create online or night courses on genetics and cell signaling to update physicians on the latest advances in cell signaling, genomic / proteomic markers, and how to effectively utilize novel discoveries in pharmacogenetics and molecular medicine. (i) The cost of such is suggested to be paid for by health care provider groups or insurers; as well, the government could provide grants to these physicians and/or educational institutions to pay for such programs. (c) Facilitate the creation of pharmacogenomic databases, through the National Library of Medicine and Department of Health and Human Services, where (1) physicians can search gene/protein-disease relationships, (2) laboratories offering tests for such associated genomic and proteomic markers can be easily found, and (3) gene/protein-therapy relationship searches are available on such databases—allowing for the effective interpretation and translation of molecular testing results to optimal therapeutic benefits for patients. (i) Collaborate with search engine programmers and journal executives to ensure the rapid integration of newly published study results showing genomic and proteomic associations with diseases, pathways, therapeutic benefits / side effects and ADME to these databases. (d) Ensure laboratories and molecular diagnostic tests offering a particular molecular profiling test, test each cell for all associated proteins and molecules in relevant cellular pathways; or, institute incentives to ensure these laboratories refer physicians, healthcare providers, or patients to where they might inquire about such associated tests. The purpose of this is to ensure a comprehensive analysis of molecular profiles is undertaken. (i) For example, if a physician treating a cancer patient inquires about EGFR testing, he/she would likely also want to test MET expression, as MET is a proven resistance factor to EGFR therapy (even if you have an over-expression of onco-protein EGFR, if you have MET over-expression you may not want an EGFR inhibitor). 2. Ensure molecular diagnostics are incorporated into, and are economical for, healthcare provider and insurance agency policies regarding coverage and use. (a) Stimulate research for novel, cost-efficient molecular diagnostic technologies. (b) Require therapy sponsors to develop pharmacogenomic and companion diagnostic tests for their therapy, if it is granted marketing approved from the Food and Drug Administration.B. Create a centralized system where we gain an understanding of different therapeutic responses to different molecular profiles, allowing us to isolate the molecular causes of rare side effects (i.e., 1 in 100,000 people may have a deficiency to metabolize a 7
  8. 8. therapy, which will not be discover in most clinical trials) and discover molecularprofiles of patients exhibiting the most positive therapeutic responses.I. Isolate and record molecular profiles and responses to treatments in a national database, governed by the National Library of Medicine. 1. Prompt physicians to offer patients the opportunity to have a comprehensive molecular profile test, where physicians could subsequently input each molecular profile and patient response into such a public database. A potential example of the collection and reporting processes of this information follows: (i) A physician offers a patient a comprehensive molecular test for known enzymes needed to be active for the proper digestion of a therapy. The patient can choose to submit the results of this molecular test to a national database to ensure, if the patient does have an adverse side effect from an unknown cause, physicians and researchers across the nation can deduce why the patient had this side effect so that others do not suffer from the same fate. (ii) The molecular test is performed. (iii) The results are collected and sent to a national database, with the physician submitting (1) the patient’s molecular profile, (2) treatment results as they occur, and (3) characteristics regarding the patient’s previous medical history, age, overall health, and other relevant data. (a) Individual’s names are not reported to maintain privacy. There must be a significant penalty for any individual or organization found to report the name of an individual to the database or any other unauthorized recipient in concert with the patient’s response or molecular profile, in order to maintain adequate privacy protection. (b) Insurers are must not be permitted to drop policies due to any genetic or molecular profiling result. (c) Molecular profiling and sending results to this database is not mandatory, but mentioned to ensure patients’ freedom of choice – discuss with medical care providers and insurers to see how they can effectively integrate offering patients the opportunity to join this database by submitting their molecular profiles and results. (d) Ensure each of our nation’s physicians and medical care providers know this database exists through using State and Federal agencies to disseminate such information.II. When previously unknown adverse side effects are discovered, the database must be flagged and an investigation must ensue to discover the cause of this effect. 1. This investigation can be to the extent of looking at that particular person’s specific traits, looking at a broad search of people with those traits and their response to similar treatments, or facilitating the construction of an experiment to discover why the adverse effect occurred. (a) If the side effect is grave, as defined by the Secretary of Health and Human Services (“Secretary”), a warning needs to be placed on the 8
  9. 9. therapy that must be shared with patients until the cause of this side effect is isolated and discovered. (b) This hold can be taken off once the cause of this side effect is discovered and controlled, but must be explained to patients by a pharmacist upon filling the respective prescription. (c) New labeling to account for the specific cause of this side effect should be placed, as defined by the Food and Drug Administration or Secretary, once the cause of the side effect is isolated and discovered. III. This database needs to be public and available to physicians and patients. 1. Governance of this site needs to be unbiased. 2. This site is to display every condition, illness, disease, and symptom, with each symptom broken down into variants in molecular expression, as such information becomes available. 3. It is suggested database submissions are by medical professionals only, each given their own identification number. Patient names must be left anonymous and not collected by the database to ensure patient participation and privacy. 4. Appropriations will be needed to build, implement, and govern this system.C. Disseminate databases and resources to best utilize the benefits of molecular medicine, annually, to all physicians through state medical boards.D. Off-label Prescription I. It is paramount therapies are NOT prescribed for indications differing from their exact approved indication, unless 1. The patient in question, or power of attorney, produces and signs a written document stating they are aware the therapy prescribed was not tested for the particular indication prescribed (dosage or illness); they accept the risks associated with this off-label prescription, recognizing this therapy as having unproven benefits and unknown consequences for the prescribed indication, and this document is signed by the patient’s respective physician and a witness. (a) Regulations and statutory penalties must be enacted to ensure pharmacies, and other therapy providers, adhere to the need for this document of consent.CONCLUSION The promise of molecular medicine is nearly incomprehensible in its benefits;while, the results of inaction are, in many cases, inexcusable in the loss of patients’ lives.We must act now to create and stimulate an infrastructure where physicians, healthcareproviders, researchers, medical journals, and database managers are able to actively andrapidly translate the benefits of molecular-based medicine to healthcare providers andpatients. We look forward to a comprehensive discussion on the merits of what we haverecommended, and we will participate vigorously in this discussion. 9

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