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

1. INNOVATION AND CHOICE
REPORT ON THE PROMISE OF AND IMPEDIMENTS TO
MOLECULAR MEDICINE
Executive Summary
Innovation and Choice
(202) 556-0614

2. EXECUTIVE
SUMMARY
Executive Summary • Molecular Medicine
WE PRESENT THE NARRATIVE of this report and the recommendations which
flow from it to the United States Congress, the President of the United States, relevant
agencies, and the American public for their consideration. This report is the product of
years of discussion with statisticians, economists, researchers, physicians, patients, the
general public, and molecular medicine experts.
The promise of molecular medicine is great. By treating patients based on the
molecular attributes of their disease and unique patient molecular profiles, optimal
therapeutic choices and personalized medicine will come to fruition. However, this
promise needs not just money, but crucial infrastructural database creations to facilitate
the transfer of valuable knowledge from relevant studies. Once this infrastructure is
created, the innovative results of research can be rapidly translated into clinical benefits
to patients. As will be illustrated, this translational of knowledge to physicians, and thus
patients, is fundamental to molecular medicine’s integration into the standard of care.
CURRENT MEDICAL PRACTICE
Diagnostics
When you go to your doctor he or she will ask you what is bothering you, perform
a physical examination, as well potential imaging and laboratory tests, all in an attempt to
narrow 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 the
examining physician believes he or she has reached the correct diagnosis. A physician
will also consider his or her past experience, and associations of various symptoms with
certain illnesses and infections, in diagnosing his/her patient. The more serious the
suspected illness or infection, the further a physician is likely to go in laboratory and
confirmatory 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 the
symptoms presented (‘clinical symptoms’), he or she will prescribe a treatment for that
suspected illness. If this treatment does not work, he or she will repeat this process, or try
a different dosage; thereby, gathering new information, hypothesizing a new illness to
account for the patient’s symptoms and laboratory results, and prescribing a treatment
based on this new hypothesis until the patient improves. This is known as the
hypothetico-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,
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3. repeating the process until the patient improves.” -- American Medical
Association
One of the most difficult aspects of this process, for physicians, is that many
patients often display common clinical symptoms which originate from different causal
molecular pathologies (diseases). This is often due to altered genomic (gene) and/or
proteomic (protein) expression levels in different subtypes of disease, leading many
doctors to believe they know what condition a patient has, prescribe a medication, and be
wrong multiple times; hence, prolonging the time for patients to receive optimal
treatments – something that is crucial when dealing with serious illnesses like cancer or
Alzheimer’s.
Therapeutic Safety and Efficacy
Pharmacological treatments (drugs), if administered orally or by any means other
than intravenously, are broken down (metabolized) by the body into subsequent
chemicals, which are then converted into other chemicals, which (hopefully) ultimately
act solely upon the diseased cells, infectious cells, or over-expressed / under-expressed
extra/intracellular molecules. How the human body absorbs, distributes, metabolizes and
excretes 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 a
therapy’s pharmacodynamics. It is important to note many therapies have an attraction,
or ‘affinity,’ for multiple molecular sites, binding and affecting multiple different
signaling pathways within a cell and patient, post administration. This consequential
binding 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 and
pharmacokinetics—together called pharmacology—are different with slight genotypic
and phenotypic variations within each cell and each person. This means variations in
genes and proteins expressed by each cell, in each respective person, will affect how well
and if a therapy will be absorbed, distributed, metabolized or excreted from a person’s
body, as well how effective each therapy’s mechanism of action will work on each
patient (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 are
prescribed 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
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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 MEDICINE
What is it?
Molecular medicine refers to methods allowing physicians to diagnose and treat
patients at the molecular level. This is realized by taking a sample of cells from a patient
and analyzing this sample at the genomic and proteomic level, looking at expression
levels of, mutations to, and slight variations in genes, proteins, and various enzymes
known to be associated with certain types of diseases/infections, symptoms, and
pharmacological characteristics (i.e., ADME and therapeutic effectiveness).
To fully understand the benefits molecular medicine offers, it is important to
remember that every process occurring in our bodies can be broken down to molecular
attributes governing it – whether that is a reaction to a drug, metastasis of cancer, or
resistance development to antibiotics. Hence, the importance of molecular testing is the
ability to isolate the underlying molecular attributes causing each person’s clinical
symptoms (and any side effects), thereby allowing clinicians to match available
treatments with those molecular causes, as most pharmacological agents have known
molecular mechanisms of action. In addition to this diagnostic-therapeutic matching,
molecular testing offers to many additional benefits to quality patient care.
Benefits from Molecular Medicine
a) 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
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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
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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% of
medical professionals dealing with cancer prescribe medications on an off-label basis –
meaning for an indication other than the approved and tested indication of a given
therapy. Two problems exist here – (1) patients believe these therapies are tested for
safety and effectiveness for the indication prescribed, and (2) disease resistance to the
therapy occurs if the therapy is not specific and sufficiently potent to the target disease or
infection.
This issue would be slightly less important, but patients are often not informed
such 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 have
proven benefits and a lack of observed side effects. However, in the case of off-label
medications, the therapies prescribed do not have proven benefits or a lack of observed
side effects for the indication prescribed.
While physicians often have valid reasons to suspect these therapies may be
beneficial for patients on an off-label basis (and, hence, prescribe them to patients), it is
important to share with patients the knowledge these therapies which are prescribed have
a lack of proven efficacy and safety for the prescribed dosage or indication.
RECOMMENDATIONS
GENERAL
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.
OUTLINE
A. 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
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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
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8. therapy, which will not be discover in most clinical trials) and discover molecular
profiles 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
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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, healthcare
providers, researchers, medical journals, and database managers are able to actively and
rapidly translate the benefits of molecular-based medicine to healthcare providers and
patients.
We look forward to a comprehensive discussion on the merits of what we have
recommended, and we will participate vigorously in this discussion.
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