This executive summary recommends creating new FDA approval pathways and incentives to stimulate the development of drug cocktails (combination therapies). It proposes 3 new approval types: Type A-1 for therapies with statistically significant results; Type A-2 for therapies that show effectiveness at the molecular level but not overall outcomes; and Type B for indications when molecular profiling is unavailable. The report argues this would help make safe, effective therapies available for drug cocktails while reducing costs for sponsors. Examples show drug cocktails have successfully treated HIV, Alzheimer's, and some cancers by targeting diseases through multiple mechanisms.
Following file comprises of information about interactions taking place between herbs-drug, herbs-herbs, it also highlights some of the cases of clinical laboratory test interactions taking place due to use of herbal medicines.
Following file comprises of information about interactions taking place between herbs-drug, herbs-herbs, it also highlights some of the cases of clinical laboratory test interactions taking place due to use of herbal medicines.
DRUG DISCOVERY & DEVELOPMENT PROCESS, it's a detail description about how drug is made available in market it's development and discovery of drug The Hole Study is given in This Topic.
Abstract
Search board and discussion:
Rational use of drugs
Antimicrobial action and spectrum
Patterns of irrational use of antibiotics
Mechanisms of antibiotic resistance
Etiological factors of irrational use of antibiotics
Impacts and complications of irrational use of drugs in general
Examples of common misused antibiotics
Solutions and Recommendations
Pharmacological Approach to Drug DiscoverySuhas Reddy C
For better understanding of students. This will give you a detailed explanation of Pharmacological approach. Contact me through comment section if you need any assistance in understating
DRUG DISCOVERY & DEVELOPMENT PROCESS, it's a detail description about how drug is made available in market it's development and discovery of drug The Hole Study is given in This Topic.
Abstract
Search board and discussion:
Rational use of drugs
Antimicrobial action and spectrum
Patterns of irrational use of antibiotics
Mechanisms of antibiotic resistance
Etiological factors of irrational use of antibiotics
Impacts and complications of irrational use of drugs in general
Examples of common misused antibiotics
Solutions and Recommendations
Pharmacological Approach to Drug DiscoverySuhas Reddy C
For better understanding of students. This will give you a detailed explanation of Pharmacological approach. Contact me through comment section if you need any assistance in understating
Fixed dose combination products – rationality, status in india, development i...Dr Sukanta sen
The development of FDCs is becoming increasingly
important from a public health perspective.
•They are being used in the treatment of a wide range of
conditions and are particularly useful in the management of
human immunodeficiency virus/acquired immunodeficiency
syndrome (HIV/AIDS), malaria and tuberculosis, which are
considered to be the foremost infectious disease threats in the world today.
Rational Use of Medicine_Evidence Based Medicine_Therapeutic Drug Monitoring_...Dr Jeenal Mistry
Rational use of Medicine: Irrational use of medicines is a major problem worldwide. WHO estimates that more than half of all medicines are prescribed, dispensed or sold inappropriately, and that half of all patients fail to take them correctly. The overuse, underuse or misuse of medicines results in wastage of scarce resources and widespread health hazards. Examples of irrational use of medicines include: use of too many medicines per patient ("poly-pharmacy"); inappropriate use of antimicrobials, often in inadequate dosage, for non-bacterial infections; over-use of injections when oral formulations would be more appropriate; failure to prescribe in accordance with clinical guidelines; inappropriate self-medication, often of prescription-only medicines; non-adherence to dosing regimes.
Evidence based medicine: Evidence-based medicine (EBM) is "the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients."The aim of EBM is to integrate the experience of the clinician, the values of the patient, and the best available scientific information to guide decision-making about clinical management. The term was originally used to describe an approach to teaching the practice of medicine and improving decisions by individual physicians about individual patients.
Therapeutic drug monitoring: Therapeutic drug monitoring (TDM) is a branch of clinical chemistry and clinical pharmacology that specializes in the measurement of medication levels in blood. Its main focus is on drugs with a narrow therapeutic range, i.e. drugs that can easily be under- or overdosed.
What do patients' need, right now, at this very given moment? It's an excellent question, which--if we mean to actually achieve--we should narrow down to a few concise and relevant points.
Paramount to the deconstruction of patient needs is understanding what the goal for patients is. This goal isn't just to live. It's to live well. It's to contribute to and enjoy the world -- to have hike the mountains, enjoy the breeze of the oceans, bask in the heat, laugh with friends, love our partners, and grow as a person.
Now, moving slowly from the goal to the respective problems. We have patients who are ill once or twice and are then relatively healthy, healthy patients who see their doctor once a year for a checkup, chronically ill people who live for the rest of their life with chronic conditions like Crohn's or Hyperthyroidism, and there are terminal patients dealing with life threatening illnesses. Certainly, there are many many more subsections of patients.
The needs for each of these segments are varient - varying along a spectrum with healthy patients needing less than the chronic and the chronic needing less than the terminal. Some people happen to be further along this spectrum than others. At the end of this presentation, we announced a survey to enumerate and articulate these needs across these various spectrums. It is our hope that this survey helps illustrate these pieces along the timeline, allowing us to focus on perfecting each piece.
My hope is for this deck to motivate people when they're down. Because, I've been down and one of the very few things that has kept me going is the knowledge that there is a next time and I can do better -- if I put in the effort. This presentation is a story of opportunity and diligence.
Developing Yourself Professionally and Personally, through starting a nonprofitRyan Witt
Here is a presentation I gave to my old club at UC Irvine about the journey I took in starting a nonprofit, and what I learned both personally and professionally. This includes lessons learned in starting a nonprofit and life lessons to take note. Hope it gives you value!
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
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1. INNOVATION AND CHOICE
REPORT ON THE PROMISE OF AND IMPEDIMENTS TO
DRUG COCKTAILS
Executive Summary
Innovation and Choice
(202) 556-0614
2. EXECUTIVE
SUMMARY
Executive Summary • Drug Cocktails
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, applicable
agencies, and the American public for their consideration. This report is the product of
numerous 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 in
defeating dynamic and debilitating conditions like cancer, ALS, and Alzheimer’s, it is
imperative that we recognize the benefits of combination therapies (i.e., drug cocktails)
and create statutory incentives to stimulate the development of such combinational
products.
These cocktails are likely to result in lower side effects and greater effectiveness
when compared to conventional therapies, as they can attack multiple different sites of
the same cellular-signaling cascade and multiple different molecular problems unique to
diseased/infected cells, at one time, leading to lower dosages needed for each molecular
mechanism to get the same or greater of an effect on the aggregate (survival or disease
response). With this in mind, it is paramount to medical progress that we stimulate the
amount of drug cocktails investigated.
BACKGROUND
What are Combination Products
A combinational product, as defined by 21 CFR 3.2(e), refers to the combination
of two or more separate components—be it drugs, devices, or biological products (a
substance derived from a living organism)—for the purposes of obtaining a primary
endpoint. 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. (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 for
Designation where the Food and Drug Administration (“FDA”) then decides which
department has oversight over that therapy. This decision of department designation is
based off the primary mode of action (PMOA) of the therapy, which is determined by an
algorithm if one is not able to determine, arbitrarily, which component is the primary
agent of action of the therapy.
BENEFITS FROM COMBINATIONAL PRODUCTS
Combination 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 IS
IMPORTANT
1. Combining already approved therapies through off-label prescription /
physician created cocktails
Currently, the FDA provides no oversight over off-label prescription. Once a
therapy is approved for use, it can be prescribed for any indication and at any dosage.
3
4. This freedom allows physicians to concoct their own cocktails of therapies, which is
ever-present in the field of cancer. It is estimated that 60% of oncologists prescribe
therapies on an off-label basis. The reason for this is because cancer is a disease of
multiple molecular dysfunctions at the root of cell-growth. Recognizing multiple means
of combating this disease, physicians often prescribe multiple drugs for cancer patients at
a time.
The downside to this off-label prescription is these cocktail therapies were not
tested in concert for safety and efficacy. This means the dosage and cocktail prescribed
may easily result in deleterious side effects. As well, physicians are not trained to make
their own dosage recommendations, thus discovering the right dose for each individual
component 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 for
each individual component. This leads to a prolonged time for society to realize the full
benefits of combination therapies, which in the case of seriously compromising illnesses
means countless lives lost.
Examples follow:
Atripla refers to a drug cocktail which combined and tested three already
approved therapies for HIV. This therapy combination of antiretroviral components
severely impedes the progression of HIV by attacking it at multiple points in its life-
cycle.
Many chemotherapy combinations for cancer are also developed by performing
clinical trials with an already approved chemotherapeutic agent along with an
investigational 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 be
isolated and proven to contribute to the overall benefit of the therapy. Safety is an
additional concern because, as these therapies are more potent, they are also more likely
to have adverse side effects. This is why the dosage of cocktails is often 10% less than
the dosage would be if each therapy was approved for use individually. The key benefit
of cocktails is the ability to specifically target a disease, infection, or condition, with
many small targets each hitting that one disease/infection site. In turn, this realizes a
grand, gestalt effect on defeating many diseases and infections.
However, with this specificity also comes with the less desired goal of a smaller
sales market for pharmaceuticals and therapy sponsors to extract profits; thereby, creating
a disincentive to produce such a cocktail unless the sponsor knows it will still reach a big
enough population. This does not appear to be the case in most instances, as sponsors
continually show they would rather test a therapy separately, have it be approved, and
4
5. then work a cocktail, than test the cocktail originally. This is evident in the case of
FUS1/p53 dual gene therapy and MD Anderson’s choice to test each therapy individually
rather than in concert despite obvious synergistic effects in mice.
It has been well documented that a therapy sponsor’s goal is to extract the most
profits possible, while providing small changes to already approved therapies to gain
additional patent protections. Over three-quarters of all drugs approved by the FDA are
new combinations or formulations of therapies rather than new chemical entities. This
means that after a therapy is developed, sponsors try to add to it rather than discovering
novel treatments.
In an effort to secure market exclusivity, sponsors will not develop cocktails until
they have the patents on each component or such components are already approved. The
reason is because the investigation of two unproven and untested components is viewed
as too risky with regards to unforeseen severe side effects, and sponsors would rather
secure each individual patent separately before investigating a cocktail to realize broader
market bases for each.
If a therapy is already developed and approved, a sponsor already has the
marketing exclusivity for that market; thus, additional cocktails are tested after these
pharmaceuticals have a lock on this market. The reason a sponsor would rather have this
than a combination therapy approved is because a single active agent is potentially
beneficial for multiple ailments rather than just a few. The more specific the therapy (the
more 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 new
chemical entities. The reason for this is likely because sponsors would rather gain
marketing 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 PRODUCTS
HIV
Drug cocktails are most commonly known in the field of HIV, with many patients
afflicted taking a treatment cocktail of three to four antiretroviral therapies. This unique
combination of active components, working in concert, has the effect of drastically
reducing HIV life-cycle by impinging on different points in this life-cycle. These
cocktails can be taken as four separate pills which must be monitored distinctly, or
together in the form of one pill and one dosage. As the human body does not have
beneficial viruses, these have very few side effects.
Alzheimer’s
Alzheimer’s is thought to be caused by the accumulation of amyloid-beta plaque
in brain cells. However, studies show this toxic protein is reduced when either of
enzymes beta-secretase or gamma-secretase are inhibited. It has also been discovered
that overly inhibiting these enzymes produce dangerous side effects – inhibiting too much
gamma-secretase leads to developmental defects, skin tumors, and a shortened life span;
5
6. while inhibiting too much beta-secretase impairs nerve function and causes
schizophrenia-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-secretase
and gamma-secretase. This reduced the production of amyloid-beta plaque, without
adverse side effects.
Cancer
Effectiveness
It is said the reason there is no cure for cancer is because cancer is not one
disease, but multiple diseases. What physicians and researchers mean by this is the fact
that cancer is simply the uncontrolled overgrowth of any cell in your body, but the cause
of this uncontrolled overgrowth is rooted in multiple different molecular dysfunctions in
the same cell. Moreover, when a cancer cell divides, those newly formed cells have
different mutations than the previous. This creates an environment where there are
multiple different types of cancer in the same very patient. To effectively combat this
ailment, it is hypothesized by many physicians and researchers that drug cocktails and
vaccines are adept to this challenge via their special ability to target specific molecules
within a cell.
Targeting potent therapies to avoid toxic side effects
Combining plasmodium (bacterial) proteins specific for liver cells with
chemotherapeutic agent doxorubicin, researchers at the University of California, Irvine
are able to specifically target liver cells with this combination therapy, effectively
minimizing 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 by
the FDA
Often times when individual therapies are not beneficial in combating illnesses,
infections, and diseases, combination products will realize desired effects. Hence, there
is 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 as
potential combination therapies.
Many therapies do not meet the FDA’s statistical cutoff for efficacy on primary
endpoints, but still provide valuable benefits to patients with little to no side effects. The
therapies I speak of are those that provide a three month benefit to cancer patients instead
of four. While it is not clear if these therapies provide benefit to patients better than
chance would (which is the purpose of statistical testing), many of them do perform their
function (inhibit telomerase or a specific kinase) at a statistically significant level. This
means that they do what they’re supposed to at a significant level, but the level of benefit
to patients’ survival rate or disease progression isn’t as grand as what is necessary to get a
therapy approved. It is proposed that these therapies should be allowed for marketing or
licensing under a separate approval type. The reason for this is because these therapies
are 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. 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. 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 has
been proven that side effects can be minimized and effectiveness maximized. As seen,
there are many ways to develop such combinational therapies – physicians can develop a
cocktail from already approved therapies, sponsors can investigate novel cocktails from
already approved therapies, sponsors can investigate novel cocktails by combining
investigational therapies with already approved therapies, or sponsors can investigate
combination therapies consistent of completely new active components. We have also
seen that it is crucial to the benefit of society at large, if a firm knows a cocktail to be
more beneficial than treatment by individual components, that firms investigate that
cocktail first and foremost. Society cannot have companies developing therapies
individually despite knowing there are better benefits to be developed, just so that
company can have patent protections for a larger market.
Given this, and the notion individual therapies in investigation which do not yield
statistically significant marks with regards to primary endpoints like survival and disease
regression, but are safe and effective in their target action, it is imperative we rewrite the
approval codes to be consistent with such knowledge. And, while we are naturally averse
to change, it is for the benefits of society at large that we must create incentives and
regulatory changes to realize the benefits of combination products.
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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