Managed Access

Before you read this post: I’m about to weave a long story that might take 20 – 30 minutes to read.  I start with recent good news before walking us back to 1953 and some phenomenal science that followed to allow this good news.  Next, I add a ‘crash course’ that covers the steps from drug discovery and development through to clinical trials, regulatory submission and approval to commercial marketing.  I’ll gloss over some things to simplify, but I do cover a lot, so read on at your own discretion.

Some good news

On June 12, 2024, I joined a group of patients in getting early access to a new medication not yet approved anywhere but submitted to multiple health agencies for anticipated regulatory decision in August.  It might sound familiar because I wrote about the February 20, 2024 regulatory submission in an earlier post.  After pre-clinical work and results from Phase I and II trials, efficacy results from the Phase III ‘Indigo’ Clinical Trial showed that “vorasidenib significantly improved progression-free survival and delayed the time to the next intervention” ⁽¹⁾, which supported Servier Pharmaceuticals in filing their regulatory submission.  Now, as part of an expanded access ⁽²⁾ period that bridges the gap between clinical trials and regulatory approval, Servier has made it possible for more patients to gain access to this new therapy while also giving an opportunity to learn more about the drug’s safety profile by closely monitoring all patients receiving treatment.  Servier used their Medicinal Product Managed Access Program (MAP) ⁽³⁾ framework for consideration under Health Canada’s Special Access Program (SAP) for drugs ⁽⁴⁾ , applicable under the Food and Drugs Regulations sections C.08.010 and C.08.011 ⁽⁵⁾.

My care team at Sunnybrook Health Sciences Centre in Toronto was connected to Indigo trial from its start and has experience in supporting patients while taking Vorasidenib as an investigational new drug; I was told that I became their first patient to join the expanded access group under the MAP / SAP period.  In this blog post, I aim to do two things:

1. share more about why the biochemist in me sees Vorasidenib as an exceptional example of science in action,
2. put my Biochemistry B. Sc, post-grad diploma in Pharmaceutical Research & Development, and my 23-year career in Pharmaceutical Product Development to use in summarizing what it takes to develop, test, and submit new drugs for regulatory approval.

As we each care for ourselves and become caregivers for those important to us, it’s likely that many of us will encounter discussions about clinical trials and new therapies while also learning about a new condition, disease, or illness we know little about.  My hope is that the latter part of this post might offer some broader context – if this sounds interesting, read on!

Vorasidenib Managed Access Program / Special Access Program

I’ll start this section with a reference back to my January 2024 blog post where I described why it was an “exciting time for Low Grade Gliomas”.  In that post, I shared my excitement as I learned about the science that had happened in the years after I studied Biochemistry, where investments in foundational genetic research led to targeted research in many forms of cancer, including brain cancers.  Scientists began to find connections between some cancers and mutations in Isocitrate Dehydrogenase (IDH), an enzyme that plays a key role in the Citric Acid Cycle which is key in cellular energy metabolism and biosynthesis ⁽⁶⁾ – also known as the Krebs cycle after Hans Adolf Krebs was awarded the Nobel Prize in Physiology or Medicine, shared with Fritz Albert Lipmann, in 1953 ⁽⁷⁾.

By 2009, scientists had learned how mutated IDH alters the Krebs cycle such that mutated versions of the enzyme begin producing a new molecule, R(-)-2-hydroxyglutarate (2HG).  The mutated enzyme gave cells an energetic advantage, and as this new 2HG accumulated, it contributed to progression to more aggressive cancers:

“cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of α-ketoglutarate to R-2-hydroxyglutarate (2HG). … Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. … IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.” ⁽⁸⁾

This research and more now gives me a clearer understanding of how my brain cancer likely developed.  At some point, an ‘early’ precursor cell like a pluripotent cell, NG-2 glial precursor cell or Oligodendrocyte Progenitor cell randomly acquired the 394 C>T mutation in one copy of the gene encoding for IDH1, where the nucleotide change from Cytosine to Thymine meant that the IDH enzyme had the amino acid Cysteine instead of Arginine at position 132 – IDH1 mutant type “R132C”.  This cell began to accumulate 2HG that over time induced other changes such as the chromosomal 1p36 and 19q13 codeletions and associated allelic losses. ^{(9), (10), (11)}  The first mutation and subsequent accumulated changes created a cell line that began proliferating and propagating such that the extra oligodendrocytes produced gave rise to my Oligodendroglioma, designated under the World Health Organization’s classification by IDH mutation (mIDH1 R132C) and 1p36 and 19q13 codeletions. ⁽¹²⁾

I’ll step back quickly to talk about brain tumours and brain cancer:  brain tumours may form from cancers elsewhere that have travelled to the brain through blood vessels, the lymphatic system, or other means.  Such metastatic brain tumours are often referred to as secondary tumours and are the most common causes of brain cancer ⁽¹³⁾.  These can include lung cancer, breast cancer, thyroid cancer or other tumour types that have spread to the brain and begin growing and adding pressure to the surrounding brain tissue.  Other brain tumours may form directly from cells normally found in the brain, referred to as primary brain tumours, and classified by the type of tumour and how fast or aggressively it grows, referred to as the tumour grade. ^(12), (14)  The World Health Organization (WHO) grades range from Grade 1 to Grade 4, such that my brain cancer is classified as a Grade 2 Oligodendroglioma, a low grade / slower-growing primary brain cancer.

Around 350,000 people around the world receive a new brain cancer diagnosis each year ⁽¹⁵⁾, a diagnosis that comes with significant disease burden by targeting the very organ that makes each of us ‘us’ by filling our days with the experiences from our senses, capturing and retrieving memories, and allowing us to speak, understand and interact with the world and people around us.  There are over 100 types of brain tumours with different cell types and genetic characterizations ^(16), (17).  Oligodendrogliomas and Astrocytomas with mutations in IDH1 or IDH2 are rare types of brain cancer, with around 20,000 – 25,000 patients diagnosed with Oligodendroglioma globally each year – less than 5% of overall brain cancer diagnoses. ⁽¹⁸⁾

With an understanding of the mechanism behind several types of brain cancers, clinicians and scientists began work on identifying possible ways that we could take advantage of the mutated enzyme for what it is (considering its modified shape) and what it does (producing 2HG) and explored what would have been a vast number of possible approaches to using this new mechanistic understanding to find a treatment.  By 2017, Agios Pharmaceuticals had invested heavily such that the team had a direction, captured in a patent describing a base molecular structure which could be added to in multiple ways to form a large ‘family’ of related molecules with the potential to effectively target the mutated enzyme in a way that would inhibit it from working properly – using ‘what it is’ to stop it from doing ‘what it does’. ⁽¹⁹⁾  From both a pure biochemistry and more intersectional medicinal chemistry perspective, this is an elegant therapeutic approach.  Earlier research had identified genetic mutations that produced a modified enzyme which was ‘broken’ in such a way that it gave superpowers to the cells it was in, then found a way to obstruct that broken enzyme as a means of slowing down the advantage those cells now had, thereby targeting the brain cancer through the very source of its power.  One such molecule described by the template in the patents was given the project code AG-881, a molecule now known by the name Vorasidenib.

By December 2020, the French-headquartered global pharmaceutical company Les Laboratoires Servier invested their money ($2 billion, plus royalties) ⁽²⁰⁾ and resources into acquiring a line of oncology products from Agios Pharma, including AG-881 / Vorasidenib.  Servier is well-positioned to make this unique therapy available to the global community of patients who have not had any new progress in treatment options for this rare disease in decades.  Today, treatment is a choice between:

a) serial monitoring via MRI imaging in a “watch and wait” phase (with or without surgery) in a low-grade brain tumour while tumour location, size, growth, and progression are manageable ⁽²¹⁾, or

b) begin targeted radiation therapy to attack cancer cells but with known harm to surrounding brain tissue ⁽²²⁾ and where technology advances allow radiologists to adjust therapy in combination with real-time imaging to reduce – but not eliminate – the collateral damage to healthy tissue.  Radiation is prescribed in combination with decades-old antineoplastic agents which are usually themselves toxic, mutagenic, carcinogenic and teratogenic alkylating agents that harm DNA, RNA and proteins in many dividing cells in the body instead of being targeted only to the cancer cells with the mutation. ⁽²³⁾

As an elegant approach to target only the mutated version of the IDH enzyme, Vorasidenib can slow progression without causing new cancers or brain damage.  The Indigo clinical trial results I described earlier – about Progression Free Survival (PFS) and Time To Next Intervention (TTNI) – mean that this drug has already been shown to give patients more time in the “watch and wait” period before needing another intervention.  Today, the next intervention is still going to be radiation and chemotherapy, but this added time will also allow patients to watch as the science progresses with other innovative treatments, and to wait for access to new not-yet-available therapeutic alternatives.  The potential for extra time offered by AG-881 / Vorasidenib is fantastic for its potential to add years without significantly reducing quality of life.

I shared in an earlier post that “February 20, 2024 was an exciting day!” because that marked the day that Servier submitted Vorasidenib for regulatory approval, with a breakthrough therapy designation supported by a companion diagnostic test for IDH mutation, meaning a regulatory decision is due by August 20, 2024.  Less than four months after the February submission, we’re now at the point where Servier has started expanding access to this drug under their MAP and Health Canada’s SAP I described earlier.  This reminds me again how my diagnosis came at such an opportune moment with respect to the scientific and clinical progress already underway.  I’m remarkably lucky to have had my cancer appear and have been diagnosed at a time that now gives me access to this new therapy.  I’m excited also that my treatment under this extended access phase comes with frequent blood testing and follow-ups that get reported back to Servier and add data to their drug safety database.  My experience will provide researchers more data to grow understanding about the product’s potential adverse events and strengthen the safety profile for future patients.

This concludes the first part of today’s post, describing the fortuitous timing of decades of innovation overlapping with my personal diagnosis.  The rest of this post will be my ‘crash course’ on drug discovery, clinical trials, drug applications and approvals, and how this all comes together.  If it sounds interesting to you, read on!

Drug discovery

Drug discovery starts with understanding the disease, illness, or condition that needs a new therapy such that the mechanism(s) can be understood, and a drug can be targeted to interact with the mechanism in some way.  To frame this section, I’ll simplify some main aspects of biochemistry by condensing an entire textbook ⁽²⁴⁾ into a few simple points that skip a LOT.  Biochemistry focuses on the cellular and molecular chemistry that makes life and living things possible.  When scaling to full living organisms like humans, biochemistry looks at processes that control all the things that organism does.  From taking in nutrients from food, digesting it to its basic components, absorbing those components and circulating through the body and controlling blood pressure, breathing, and right down to the controls in individual cells, biochemistry often focuses on controls that speed things up or slow things down anywhere from the cellular level up to a tissue or organ, and eventually to a whole organism like a human.  The controls themselves typically exist as something equivalent to a ‘gas pedal’ that speeds something up, or a ‘brake pedal’ that slows something down.  Drugs often target these controls by activating either the gas or brake pedal as an agonist, or de-activates the gas or brake pedal as an antagonist (aka inhibitor).

To put this in context of therapeutic drugs, I’ll briefly explore processes that control blood pressure.  The heart pumps blood through blood vessels in our body and it feels intuitive to understand the pressure in these blood vessels by looking at a) how hard the heart pumps, b) how relaxed or constricted the blood vessels are, and c) the volume of blood being pumped through the closed system.  Years of research mean that we have a detailed understanding of the role our kidneys play in regulating total blood volume by retaining or releasing water, hormones that control blood vessel diameter and the heart’s pumping action, and with local effect in specific tissues and organs balanced with global whole-body effects. ^(25), (26)  We have a variety of medical agonists and antagonists as anti-hypertensive drugs such as diuretics, beta blockers, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers (CCBs) and more that either step on or block the right brake or gas pedal(s). ⁽²⁷⁾  Previous research to understand the multiple mechanisms and develop multiple targets explains why we have many treatment options for many conditions or diseases.  This variety is important when we acknowledge that we have a wide natural variation in the genes that encode the proteins and enzymes that form these controls: our individual proteins and enzymes may differ in small ways that change one specific drug’s level of effectiveness for a given person and can contribute to our own experience of adverse effects of a specific drug.

Identifying and screening the right target

After finding the control mechanism(s), the next step is to find / discover / design a molecule that might activate or deactivate the pedal we’re interested in.  This often starts with looking at the 3-D structure of the protein(s) involved along with the 3-D structure of the molecule(s) usually involved, then designing an alternate with just the right shape.  This alternate often comes in the form of an adjustable template with a core molecule where subtle changes in one or more functional group(s) can be changed to get just the right fit to have the right effect.  This usually results in thousands of possible molecules that now need to be researched and evaluated.  It takes time to develop synthetic routes capable of producing each molecule, and more time to evaluate each one.  Modern computational tools help, but it is still a large task to evaluate thousands of options.

In the case of Vorasidenib (AG-881), the naming might make us think that this was ‘just’ the 881^st compound evaluated but history tells us that would be too quick an assumption.  The drug Mifepristone has been in the news recently based on US Supreme Court decisions, but some may remember the stories in the late 1980s and early 1990s when many of us knew the research project name RU-486. ⁽²⁸⁾  That project code identified the French Pharmaceutical company Roussel-Uclaf as the drug developer, and the molecule as the 38,486^th compound they synthesized in their search for a solution. ^(29), (30)  The code name RU-486 made its way into songs like Consolidated’s 1994 song “Butyric Acid”, One Ton’s 2002 “Another Miracle”, Stone Sour’s 2012 song “RU486” and more, as examples of how these code names describing drug development can make their way into popular culture. 

I don’t expect that AG-881 will appear in song lyrics soon, and I don’t know whether this was the 2,881^st compound Agios explored, or the 13,881^st or 27,881^st or some other n,881^st compound but that it does represent a significant scientific investment.  For the thousands of candidate compounds, project team members would have had to eliminate compounds known to have potential harmful effects or potential for metabolic transformation into other harmful molecules before even testing molecules for effectiveness.  Scientists today have a suite of tools to help with screening in advanced computer software (in-silico studies) before moving to various traditional chemistry lab analyses (in-vitro studies) and testing in living organisms (in-vivo studies).  In the case of Vorasidenib, inhibitors could first be evaluated with in-vitro pre-clinical assays to assess whether a proposed compound might be effective. ⁽³¹⁾

As a complicating factor in developing drugs to treat the Central Nervous System, the blood vessels in the brain come with an added level of protection.  Blood vessels elsewhere in the body are ‘leaky’, such that they allow liquid and components of the blood to transfer into the tissues around the blood vessels, much like a soaker hose in a garden that allows water to seep out to water the surrounding soil and plants.  Even ‘large’ things like the immune system’s White Blood Cells can move from capillaries into surrounding tissue to fight infection.  In the brain though, blood vessels are more tightly connected such that larger molecules can’t leave the blood and gain access to the surrounding brain tissue.  Blood vessels in the brain act more like a typical garden hose that doesn’t leak water across its length.  This Blood Brain Barrier protects the brain from potential harm from undesirable molecules or infections but presents a challenge for drug development teams who must now find a small molecule that can gain access to the brain cells the molecule is intended to target. ^(32), (33)

After narrowing down the list from thousands of potential candidates to a smaller group for testing, scientists will typically explore the compound for potential adverse reactions (side effects) from known biochemistry and finalize a list that can proceed to Clinical Trials as the next step, where more information can be gathered about efficacy and other not-yet-known potential adverse events.  With a list of potential Active Pharmaceutical Ingredients (APIs), work moves on for further study, which is where we as patients and caregivers typically first encounter them.  In our Vorasidenib story, AG-881 was identified as a small brain penetrant molecule that had the potential to be made into an oral drug that could be absorbed in the stomach, distributed through the blood, could cross the Blood Brain Barrier and into cells throughout the body.  It could eventually come across the mutated IDH enzymes in brain cancer cells where it would compete with the active site of the enzyme and slow down the altered activity that promotes tumour progression, all without blocking the ‘normal’ – Wild Type – versions of IDH crucial for energy metabolism in all of our cells.  More work was needed to find out how safe it could be, and how well it might work, which brings us to clinical trials and studies.

Clinical Trials and Studies

In this section, I focus mostly on the traditional ‘A vs. B’ clinical trial to figure out whether a new medicine / API can have a beneficial outcome for patients.  After, I’ll broadly describe how this aligns with parallel work by teams who focus on 1) the drug substance and the processes to scale up API synthesis from lab to commercial scale, and 2) the drug product by developing the final tablet, capsule, injection, or other dosage form that will eventually be made available to patients.

In general, the design of pre-clinical and clinical trials begins with an approach to minimize potential harm to participants while growing knowledge about the efficacy of an API and its final dosage form and learning about the safety profile through appropriate strength and by collecting information about potential adverse reactions and events that most of us refer to as side effects.  With a knowledge of the condition being targeted and the mechanisms involved, researchers adjust study design at each phase to best achieve research goals while minimizing risk to any trial participants.  Generally, trial designs fall into the four (or five) phases I summarize in the table below, where researchers will customize the trial approach and phases to meet the unique needs of the patient population and condition intended to be treated by the drug being developed: ^(34), (35)

Phase	Purpose and Description	Typical sizing, comments
Preclinical	Target screening, described above where teams use in-silico and in-vitro studies to screen targets.	Thousands of molecules, no human participants but potential for cellular or animal testing.
0	Initial subtherapeutic evaluation of in-vivo Pharmacokinetics (PK)* and Pharmacodynamics (PD)*	Few participants, probably a number close to 10 or so.
1 / I	Dose-ranging studies to find a broad tolerable range, starting at a low dose before increasing while monitoring for any progressive or new adverse reactions.  This phase often evaluates possible dosage forms (IV, injectables, tablets, capsules, creams, or other forms) and focuses on dose tolerability.	Still small, but more likely to be tens of people (e.g., perhaps 20, 30, 50 or more), focusing on healthy volunteers screened appropriately to maximize safety while learning about adverse reactions.
2 / II	Initial efficacy studies, evaluating how well the drug works, what dosing provides the optimal balance of therapeutic benefit while reducing risk of adverse events, and any special considerations around how to take the drug (e.g., with or without food, time of day, and similar items that later guide how your doctor or pharmacist tells you to use the medicine)	Slightly larger, typically with 100 or more patients with the condition to be treated, and with screening criteria to limit the potential of harm to those enrolled, such that some patients will be excluded from participation at this phase.
3 / III	Larger scale clinical efficacy trials, comparing the drug against other established standard treatment(s) and/or placebo, typically in a blinded fashion where some study participants receive the established treatment or placebo while others receive the new drug under study.  The study is designed to allow for conclusive statistical evaluation comparing the two groups, with a variety of study designs available, and gathers more information about safety and adverse reactions by including more participants.  The final biostatistical analysis will determine whether the new drug has a risk/benefit profile that can support its approval as a new therapy.	Larger, typically with many hundreds of patients involved, often exceeding 1,000 participants in multi-center trials.  This stage often includes more exclusion criteria to ensure the study can reach a statistically valid conclusion without ‘noise’ from extra variables, but usually allows more patients to participate than in a Phase II study.
4 / IV	Post-market surveillance to further monitor safety through adverse events and reactions.  This may include active and ongoing surveillance of earlier study participants through structured and solicited feedback after moving to the commercially available approved drug, spontaneous reporting by other patients or caregivers through established drug safety / pharmacovigilance reporting channels, and more.	Any patients receiving treatment after the drug receives regulatory approval and is launched for commercial availability in approved markets.
5 / V	Real World Evidence and ongoing research.  While traditional clinical trial phase descriptions end at phase IV, extended research and meta-analysis is sometimes referred to as Phase V.  Instead of focusing on specific study participants, researchers review data and reports from many available sources to learn more about ‘real world’ use.	All use of the drug, including reports of off-label use, experience in different settings (e.g., at home vs. clinical or long-term-care settings), and other published literature.

* Think of PK as the motion (kinetics) of the drug in the body – what your body does to the drug, typically in terms of Absorption, Distribution, Metabolism and Excretion (ADME), and PD as the power (dynamics) of the drug in the body – what the drug does to your body in terms of its biochemical activity and role as an agonist or antagonist for the appropriate ‘gas and brake pedals’, and the final result in a measurable outcome.

Researchers must design studies to consider impact on participants, the ability to include enough participants in studies to reach meaningful statistical conclusions while accounting for early participation attrition and other factors, all while ensuring that the studies uphold established ethical standards of care for participants. ⁽³⁶⁾

In the case of the Indigo clinical trial for Vorasidenib, the study was designed by enrolling patients who were already in a “watch and wait” stage either after or before surgical removal, who had sufficient tumour volume to be able to monitor through standard MRI imaging, and who had not already had radiation or chemotherapy that could impact their progression.  This allowed researchers to ethically assign participants to either the Placebo or Treatment arm of the study without adding risk to patients.  Under the study, participants were monitored by the same serial MRI imaging they would expect, and those images were used to decide when participants’ cancer progressed to a point requiring further treatment.  Study researchers collaborated with patient care teams such that patients on the placebo arm could be moved to the treatment arm or an alternative therapy if their scans showed the need for further intervention.  This design allowed researchers to monitor PFS and TTNI as primary measurable targets for statistical evaluation, while also collecting information about patients’ reported quality of life.  I remain thankful for the patients before me who participated in earlier clinical trial phases, including the Phase III trial that allowed researchers to gather data that demonstrated efficacy ⁽¹⁾  and supported Servier’s February 20, 2024 submission to regulatory agencies.  That submission then paved the way for the MAP / SAP access as Servier expanded into a pre-approval Phase IV study.

Scaling things up

At the early stages of clinical trial, researchers are typically working with small-scale trials of new APIs, often developed on lab benches in things that look like beakers, flasks, and test tubes that many people recognize as typical in a chemistry lab, and with batch sizes that might be measured in grams.  To scale up to the larger quantities needed for future commercial manufacturing, industrial chemists begin the work of designing large scale processes using industrial sized reactors while evaluating and reducing potential impurities like related compounds that might be produced as side products or residual solvents or reactants used in the complex synthetic routes, such that they can scale up to large batches (many kilograms) of high quality, high purity drug substance to be later turned into the final drug product to be dispensed by pharmacies upon approval.

This means that there is one team working on the API, the drug substance that supplies the pharmaceutical effect – the Ibuprofen in Advil, and a second team working on the final dosage form, the drug product that patients will eventually take – the Advil tablet that contains Ibuprofen.  Ideally, the teams work in tandem, and adjust their work as they learn more during progressing clinical trial phases.  The drug product development team finds potential ingredients and formulations typically used for the desired dosage form, evaluates for any compatibility issues where an ingredient might degrade the drug substance, and ideally gives feedback to the industrial chemists to describe the optimal characteristics like particle size, crystal structure, bulk powder density and flowability and more.  As the drug substance team scales up their synthetic process, it may change the bulk qualities of the finished batch that impact the drug product team as they also scale up from something like a ‘test kitchen’ scale batch measured in grams to the future industrial scale batch in hundreds of kilograms.  Both the drug substance development and drug product development identify the critical processing controls and parameters and the quality attributes that can be tested for to confirm the final product is suitable for its intended use.  Both teams work on the Chemistry and Manufacturing Controls (CMC) that identify the design space in an approach commonly referred to as Quality by Design (QbD) with a series of experiments and trial batches prepared to fully understand the processes in making both Drug Substance and Drug Product so that variations in raw materials and processing steps are fully characterized to ensure repeatable future full-scale production. ^(37), (38)  As results come in from Clinical Trials, changes might be needed to the Drug Product formulation and / or manufacturing steps, while the development teams also evaluate the long-term stability of the finished product and prepare the documentation needed to submit for regulatory review and approval – all while the clinical trials and studies continue.

New drug submissions / applications

Historically, a New Drug Application (NDA) to the US FDA, a New Drug Submission (NDS) to Health Canada, and similar applications to other global Health Agencies (HAs) were filed as large document collections typically sent in bankers’ boxes with over 100,000 pages, but now filed digitally in an electronic Common Technical Document (eCTD) structure with a similar ‘page count’ now interconnected and managed for regulatory review. ^{(39), (40), (41)}

The submissions are formatted with an overall summary in Module 2 to guide reviewers with a high-level review of what’s ahead in the detailed sections that follow.  Module 3 covers all Quality aspects and CMC details for both the Drug Substance and Drug Product, including the development process

from initial trials to future intended commercial production.  Module 4 focuses on safety, including non-clinical reports capturing pharmacology details, PK information, Toxicology and more.  Module 5 includes detailed reports from the clinical studies demonstrating efficacy and product suitability for its intended use.  The structure is detailed by the International Council for Harmonisation (ICH) and summarized in the triangle image product development and regulatory teams around the world are familiar with. ⁽⁴²⁾

When the submission is made to a Health Agency, the HA assigns resources with the skills necessary to review the applicable sections and often collaborates with other multidisciplinary groups for specialized reviews.  Health Canada, for example, works with a pan-Canadian health organization now known as Canada’s Drug Agency / L’Agence des médicaments du Canada (CDA-AMC).  Formerly the Canadian Agency for Drugs and Technologies in Health (CADTH), it was set up to “[coordinate and align] public value within Canada’s drug and health technology landscape.” ⁽⁴³⁾  They in turn set up advisory bodies like the pan-Canadian Oncology Drug Review (pCODR) Expert Review Committee (pERC) ⁽⁴⁴⁾ who focus on oncology pharmaceuticals and make recommendations during review and at approval.

During review, the Health Agency shares any identified deficiencies with the company sponsoring the application so that the Sponsor and the HA can evaluate the science supporting the application and to either correct deficiencies or supplement the application with new information where needed.  It is a comprehensive review often with multiple ‘back-and-forth’ interactions with a goal of assuring patient safety while giving patients access to new therapies that offer benefit and hope.

During this back-and-forth, the Sponsor will prepare internally for the commercial production activities they have already described in Module 3.  They will assess raw materials against their established specifications, dispense and manufacture initial batches and conduct detailed testing that includes final specifications and added tests designed to evaluate the success of scaled up production batches.  They time this work to a predicted positive regulatory decision (approval by the HA) and prepare their production teams to package and label the final drug product, then to transport to distribution centers and pharmacies to align with a final approval date.

Specifics of the final approval will vary by country and Health Agency but may include conditions or limitations for use by specifying or excluding identified populations through the indications and contraindications for use, and typically set up pricing and reimbursement criteria.  In Canada, for example, the Patented Medicine Prices Review Board (PMPRB) reviews and monitors prices charged by patentees, may pre-approve pricing though pre-approval is not a requirement, and investigate when prices appear to exceed guidelines. ⁽⁴⁵⁾  They assess therapeutic benefit compared to existing treatments and use this as input into pricing standards and guidelines.  As Health Canada approaches a decision on the submission, CDA-AMC times their review to align as best as possible and collects input from stakeholder groups before making a draft recommendation for reimbursement under provincial drug plans.  The non-binding recommendations then move to provincial drug plans to establish final reimbursement conditions listed in provincial formularies. ⁽⁴⁶⁾  Listing in the formularies then guides whether a provincial drug plan will provide funding, and establishes conditions for third party drug benefit plans.

Bringing this back to Vorasidenib, Servier submitted their application on February 20^th, which began activity toward an August 20, 2024 decision given the assigned breakthrough therapy designation.  Having completed Phase III clinical trials, Servier engaged their Managed Access Program allowing expanded access to patients like me, before full approval, and as part of early data gathering under Phase IV studies.  I see this Expanded Access under Health Canada’s Special Access Program as a clear demonstration of how the executive team uses the combined resources at Servier to the benefit of patients.

The team at Servier is now preparing their full-scale manufacturing process to make ^PRVoranigo™ tablets as the drug product containing Vorasidenib as the API / Drug Substance.  Teams are testing the incoming ingredients, sampling, and testing at various steps in their manufacturing process, and are packaging the tablets with the necessary protection to maintain shelf life and the printed material to help patients as they begin therapy, and with additional information to assist clinicians and pharmacists as this new product comes to market.  This drug is more than just a new treatment for patients, it is hope for more time and a better quality of life in the face of a terminal diagnosis.  It offers an opportunity to delay the harmful effects of existing therapy and time to wait for science to progress to the next new treatment option.  I remain fully optimistic, and with a sense of just how fortunate those of us with Astrocytomas and/or Oligodendrogliomas are to have this new possibility about to be available for use, and excitement for what the coming years will offer.

  

Works Cited

1. Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma. Mellinghoff, Ingo K., et al. 7, s.l. : Massachusetts Medical Society, August 17, 2023, New England Journal of Medicine, Vol. 389, pp. 589 - 601.

2. Servier US | Les Laboratoires Servier. Expanded Access. Servier US. [Online] 2024. https://servier.us/expanded-access/.

3. Servier | Les Laboratoires Servier. Servier - Medicinal Product Managed Access Programs. servier.com. [Online] 2024. https://servier.com/en/research-innovation/medicinal-product-managed-access-programs/.

4. Government of Canada. Health Canada. Health Canada's special access programs: Overview. [Online] 02 15, 2023. https://www.canada.ca/en/health-canada/services/drugs-health-products/special-access.html.

5. Government of Canada . Food and Drug Regulations (C.R.C., c. 870). Justice Laws Website. [Online] 06 11, 2024. https://laws-lois.justice.gc.ca/eng/regulations/c.r.c.,_c._870/index.html.

6. Pelley, John W. Citric acid cycle – an overview. Elsevier's Integrated Review Biochemistry. 2nd. Philadelphia : Elsevier, 2012, 7, pp. 57-65.

7. Nobel Prize Outreach. The Nobel Prize in Physiology or Medicine 1953. The Nobel Foundation. [Online] 2024. [Cited: 6 17, 2024.] http://nobelprize.org/nobel_prizes/medicine/laureates/1953/.

8. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Dang, L., White, D., Gross, S. et al. November 22, 2009, Nature, Vol. 462, pp. 739 - 744.

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