New Guidelines on Patent Eligibility for Subject Matter Derived from Nature

Contributed by: Jack Snyder, MD, PhD, RAC, DABT, CPI
Asst. Managing Director
CATO Research Washington

United States Patent & Trademark Office Issues New Guidelines on Patent Eligibility for Subject Matter Derived from Nature

An important new guidance memorandum from the United States Patent and Trademark Office (USPTO) entitled Guidance For Determining Subject Matter Eligibility Of Claims Reciting Or Involving Laws of Nature, Natural Phenomena, & Natural Products (Guidance) implements a new procedure to address changes in the law relating to patent subject matter eligibility under 35 U.S.C. § 101. This guidance addresses the impact of Association for Molecular Pathology v. Myriad Genetics, Inc., 569 __, 133 S. Ct. 2107, 2116, 106 USPQ2d 1972 (2013) (Myriad) on the Supreme Court’s long-standing “rule against patents on naturally occurring things”, as expressed in its earlier precedent including Diamond v. Chakrabarty, 447 U.S. 303 (1980) (Chakrabarty), and Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. __, 132 S. Ct. 1289, 101 USPQ2d 1961 (2012) (Mayo). See Myriad, 133 S. Ct. at 2116. Myriad relied on Chakrabarty as “central” to the eligibility inquiry, and re-affirmed the USPTO’s reliance on Chakrabarty’s criterion for eligibility of natural products (i.e., whether the claimed product is a non-naturally occurring product of human ingenuity that is markedly different from naturally occurring products). Id. at 2116-17. Myriad also clarified that not every change to a product will result in a marked difference, and that the mere recitation of particular words (e.g., “isolated”) in the claims does not automatically confer eligibility. Id. at 2119. See also Mayo, 132 S. Ct. at 1294 (eligibility does not “depend simply on the draftsman’s art”). Thus, while the holding in Myriad was limited to nucleic acids, Myriad is a reminder that claims reciting or involving natural products should be examined for a “marked difference” under Chakrabarty.

In summary, all claims (i.e., machine, composition, manufacture and process claims) reciting or involving laws of nature/natural principles, natural phenomena, and/or natural products now should be examined using the Guidance. The new procedure set forth in the Guidance will assist patent examiners in determining whether a claim reflects a significant difference from what exists in nature and thus is eligible, or whether a claim is effectively drawn to something that is naturally occurring, like the claims found ineligible by the Supreme Court in Myriad.

According to the USPTO, the following factors should be used to analyze the claim to assist in answering Question 3 (in flowchart below) for claims reciting or involving judicial exceptions other than abstract ideas. On balance, if the totality of the relevant factors weigh toward eligibility, the claim qualifies as eligible subject matter. If the totality of the relevant factors weighs against eligibility, the claim should be rejected. The examiner’s analysis should carefully consider every relevant factor and related evidence before making a conclusion. The determination of eligibility is not a single, simple determination, but is a conclusion reached by weighing the relevant factors, keeping in mind that the weight accorded each factor will vary based upon the facts of the application. This factor-based analysis, which requires consideration and subsequent weighing of multiple factors, is similar to the Wands factor-based analysis used to evaluate whether undue experimentation is required to make and use a particular claimed invention. See, e.g., MPEP 2164.01(a) for an explanation of the Wands analysis. Not every factor will be relevant to every claim and, as such, need not be considered in every analysis.

According to the USPTO, factors that weigh toward eligibility (significantly different):

a) Claim is a product claim reciting something that initially appears to be a natural product, but after analysis is determined to be non-naturally occurring and markedly different in structure from naturally occurring products.

b) Claim recites elements/steps in addition to the judicial exception(s) that impose meaningful limits on claim scope, i.e., the elements/steps narrow the scope of the claim so that others are not substantially foreclosed from using the judicial exception(s).

c) Claim recites elements/steps in addition to the judicial exception(s) that relate to the judicial exception in a significant way, i.e., the elements/steps are more than nominally, insignificantly, or tangentially related to the judicial exception(s).

d) Claim recites elements/steps in addition to the judicial exception(s) that do more than describe the judicial exception(s) with general instructions to apply or use the judicial exception(s).

e) Claim recites elements/steps in addition to the judicial exception(s) that include a particular machine or transformation of a particular article, where the particular machine/transformation implements one or more judicial exception(s) or integrates the judicial exception(s) into a particular practical application. (See MPEP 2106(II)(B)(1) for an explanation of the machine or transformation factors).

f) Claim recites one or more elements/steps in addition to the judicial exception(s) that add a feature that is more than well-understood, purely conventional or routine in the relevant field.

According to the USPTO, factors that weigh against eligibility (not significantly different):

g) Claim is a product claim reciting something that appears to be a natural product that is not markedly different in structure from naturally occurring products.

h) Claim recites elements/steps in addition to the judicial exception(s) at a high level of generality such that substantially all practical applications of the judicial exception(s) are covered.

i) Claim recites elements/steps in addition to the judicial exception(s) that must be used/taken by others to apply the judicial exception(s).

j) Claim recites elements/steps in addition to the judicial exception(s) that are well-understood, purely conventional or routine in the relevant field.

k) Claim recites elements/steps in addition to the judicial exception(s) that are insignificant extra-solution activity, e.g., are merely appended to the judicial exception(s).

l) Claim recites elements/steps in addition to the judicial exception(s) that amount to nothing more than a mere field of use.

According to the USPTO, factors a) and g) concern the question of whether something that initially appears to be a natural product is in fact non-naturally occurring and markedly different from what exists in nature, i.e., from naturally occurring products. This question can be resolved by first identifying the differences between the recited product and naturally occurring products, and then evaluating whether the identified differences together rise to the level of a marked difference in structure. Not all differences rise to the level of marked differences, e.g., merely isolating a nucleic acid changes its structure (by breaking bonds) but that change does not create a marked difference in structure between the isolated nucleic acid and its naturally occurring counterpart. Instead, a marked difference must be a significant difference, i.e., more than an incidental or trivial difference.

As explained above (and in detail in the USPTO Guidance), the overall process for determining subject matter eligibility of all claims (i.e., machine, composition, manufacture and process claims) reciting or involving laws of nature/natural principles, natural phenomena, and/or natural products is to walk through the three questions in the flowchart below to determine whether the claim is drawn to patent-eligible subject matter. If not, then the claim is prima facie ineligible, and the claim should be rejected using revised form paragraph 7.05.13 (in Part IV of the Guidance). Importantly, the Guidance does not change examination of claims reciting an abstract idea, which should continue to be analyzed for subject matter eligibility using the existing guidance in MPEP § 2106(II).

Regulatory and legal practitioners now have a new tool for advising clients as to patent eligibility of claims relating to natural products, laws of nature, and natural phenomena. Courts may or may not agree with USPTO’s guidance, and USPTO may have to issue follow-up guidance that accords with new case law. Importantly, Myriad has asserted further claims relating to cDNA, primer pairs, and methods for detecting the BRCA1/2 mutation, while Counsyl and Quest Diagnostics have asked for declaratory judgments of invalidity and non-infringement of many of the same patents asserted by Myriad. For now, the biomedical world should watch USPTO’s handling of claims relating to natural products and laws of nature with great interest and vigilance.

New Guidelines on Patent Eligibility for Subject Matter Derived from Nature

New Guidelines on Patent Eligibility for Subject Matter Derived from Nature


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Effective Partnerships for Virtual Biotech Companies–how companies and partners can work efficiently together

Lisa R. Sanders, Ph.D., R.A.C., Sr. Clinical Scientist II at Cato Research

No matter what you call it–outsourcing, contracting, partnering–for a virtual biotech, partnership is vital to success. Virtual companies face specific hurdles such as the lack of a central office and infrastructure, a small and often geographically dispersed workforce, undercapitalization, small pipeline, and a lack of corporate SOPs. And while a good product is necessary for success, it is not itself an assurance of success. Driving product development with efficient, effective partnerships translates to a more efficient, effective development program.  Let’s look at the tale of two companies…

Slam Dunk Turned Airball

The facts:

  • Virtual company comprised of a handful of very experienced, geographically disbursed pharma professionals, all in the US. Most had 10-20+ years of product development experience in large pharma, but no prior experience in a virtual company.
  • Company acquired a product with demonstrated safety and efficacy to carry through a final pivotal Phase 3 study and submission of a marketing application.
  • Company had strong milestone-based financial agreements to support the remaining development activities.
  • Company outsourced most key development activities (CTM production and distribution, non-clinical studies, assay development and sample analysis, clinical trial management, and regulatory submissions.)

The result: Despite very experienced personnel and a product far down the development pathway, the company dissolved within about 2 years with the product still in Phase 3 testing.

What went wrong? Time was an enemy that could not be overcome–inefficiencies and disorganization was endemic. Time delays meant they were unable to attain key milestones, and the money ran out. Key contributors were:

  • Partnerships: Partners were well-chosen and solid, but not given autonomy.   Outsourced activities were “siloed” within the company with inadequate communication on intersecting activities, and the partners were allowed virtually no interaction with each other. Over-management of outsourced activities was time consuming for already very busy individuals. There was no high-level, coordinated oversight of the development activities.
  • Geography: Company was spread over home offices from coast to coast. No central office, no office-based staff, very limited personal interactions within the company or with outsourcing partners.
  • Communication: Company relied almost exclusively on email for internal and external communications. While this allowed information to be shared across all relevant parties, it came at a significant time cost. The resulting email load proved too impossible to manage and the company’s team was often not up to date on overall development activities.  Important requests or updates from partners were lost in the email overload and important decisions were delayed or never made.
  • Standard Processes: The company had no internal standard operating processes. They relied entirely on their partners’ SOPs, which is not unusual. But where there were conflicts between partners’ processes, decisions regarding which would be followed were often long in coming, slowing progress.
  • Infrastructure: The company lacked infrastructure outside of what the company personnel had in their home offices. There was no central administrative support to coordinate meetings, track schedules and travel, and track outstanding action items. There was no company IT support and no centralized file storage. Unless in an email, documents appeared to be unavailable to individuals in the company.
  • Workload: All company employees were regularly working 70+ hour weeks for >2 years. They had no back up plans in place for vacations and travel times. Outsourcing partners often had to wait for weeks or sometimes months for decisions or attention to issues. Together with poorly defined decision making processes within the company, inaction on important issues was common.

A Happier Tale–

  • Virtual company was a university spin off developing a single product from the discovery phase
  • Three full time employees, with the vast majority of day to day work done by one person
  • Funding was primarily grant-based
  • Company had a small office with administrative and IT support, where personnel could meet internally and with partners
  • All development activities were outsourced with one full service CRO coordinating activities

Result: The product moved steadily from concept through a successfully completed Phase 2 study. A collaborator is now being sought for further development.

What was different here? With fewer people, less money, and a completely unproven product, they efficiently moved the product through CMC development, pre-clinical testing, and three clinical studies.

  • Partnerships: Importantly, they utilized a full service CRO to coordinate most of the outsourced activities, giving a layer of consistent project management for the development program. The key individual at the company had adequate time for higher level planning. They managed outsourced activities at a high level, leaving the day to day details to the CRO. Also, they tended to focus on local partnerships and source activities to smaller partners. This allowed more face to face interaction and relationship development while giving their project a higher profile than it would have had with larger partners. Finally, they conserved cash by negotiating some equity for work agreements into their contracts.
  • Geography: The company had one small office and all personnel were based in that office. This facilitated communication, interactions, relationships, and decision making. The ability to easily talk to one another reduced reliance on email.
  • Communication: Email was used, but a significant amount of communication took place by phone and during regularly schedule meetings. This freed time for the company and its partners, and it prevented the email overload that leads to important communications being overlooked. Important requests were attended to quickly, allowing development to progress efficiently.
  • Standard Processes: Having a single coordinating CRO allowed that group’s SOPs to be the primary procedures followed during the development program. The CRO reviewed SOPs from other vendors that they were overseeing to ensure they were in line with the existing procedures.
  • Infrastructure: Company chose an office location that included reception, basic administrative support, and office equipment. The single office location meant everyone had access to scanning, copying, faxing, and shipping.
  • Workload: Aall company employees were still regularly working well over 40 hours per week. But, the work being done was not redundant with what was outsourced and there was time for the high-level planning activities.

The Take Away–

So what do we take away from these examples? Here are some strategies that support effective and efficient partnering relationships:

    • Partners: Choosing the right partners is key.
      • Start with a realistic assessment of what the company can really do and where help is needed. Overwork leads to a loss of focus and mistakes–sometimes lots of them.
      • Look for a good “fit”–partners experienced and interested in your product and therapeutic area whose company culture meshes well with yours. You might find cheaper services, but if they are not invested in your product, you might not get the attention you need.
      • Once you choose, trust your choice and don’t micromanage. Let them do the work you are paying for.
    • Intellectual Property Protection: IP may be the only tangible asset a virtual biotech has. When looking for a manufacturing partner, keep IP protection as a priority. Cost is important, but look also at a country’s laws around IP and the history of manufacturers in that country. Is there a history of piracy or divulged secrets? Manufactures in other geographies might be more expensive, but offer better protection for your most valuable asset.
    • Contracts: Negotiate contracts carefully—consider risk sharing, milestone bonuses, and alternative financing (e.g., payment in equity). Smaller partners may be more likely to consider these arrangements in return for a lower bottom line contract cost (plus better attention to your product).
    • Communications: Streamline your communications (internally and with partners). Overreliance on email is tempting–you can update everyone at once. But this is usually done more efficiently in routine update meetings. Document when you need to, but use the phone to save time. Don’t meet if you don’t need to–pass on the standing, weekly meeting when there is nothing important to discuss.
    • Oversight and Relationships:
      • Good relationships are motivating for your outsourcing partners. Along with appropriate oversight (including on-site visits), strong relationships help ensure the quality and efficiency of your outsourcing partner’s work and will get your project the attention it needs.
      • Be sure that all outsourced activities are overseen by an in‑house manager—while your partners will generally include project management in a contract, oversight by an in-house resource will help ensure your partner stays on track. Plus your 30,000 foot view across all development activities requires up to date progress reports.
      • Focus on program management rather than operational management–you are paying someone else for that. Micromanaging your partners is a time sink for them and for you.
      • Get to know your primary contacts. Schedule a face to face kick off meeting. Acknowledge good work when you see it; a little praise goes a long way to motivate future efforts.
      • Incentivize your partners–relationships are a primary way to do this. When they know you, your partners are more accountable for the project and your needs. Incentives can also include a bonus for attaining a key milestone–whether a contractually-specified bonus to the company, or a personal thank you with a gift card to your key contact (or both).

And if You are a Partner to a Small, Virtual Company??

  • Know your client: Who you are working with? Evaluate the company and the product before you partner. Is it a viable product with adequate funding? Meet face to face at least at kickoff to develop good relationships. For longer projects, at least annual face to face meetings are a good idea. Consider paying your own way to visit your client–the efficiencies gained in the long run will outweigh the short term expense.
  • Careful contracting:
    • Make financial risk reduction a priority
    • Consider “pay as you go” rather than milestone payments to recoup your costs in real time.
    • Consider a risk/reward arrangement to capitalize on milestones achieved. If you beat a key milestone, you receive a bonus. If you miss one, they get a discount.
  • Scope: Small companies have big needs and often push the envelope when it comes to scope. Define scope carefully and make sure you have a work order in place for all activities. Discuss upfront how out of scope activities will be addressed and who needs to approve new work.
  • Communications: Email overload kills efficiency. Use the phone for day to day issues and save the email for times when formal documentation is needed. Stop the crazy email chains by scheduling a short teleconference to discuss issues with all stakeholders at the same time. Virtual employees can be very busy–follow up until you get an answer and don’t let issues languish.
  • Logistics and infrastructure: Virtual companies may lack administrative or IT support. Be ready to act as the coordinator for meetings and teleconferences, to set up a secure portal to house documents, and provide other administrative support (e.g., shipping, document compilation) to keep things moving efficiently.
  • Decision making: At the start decide who is responsible for what and write it down. Hold your client contact accountable to these decisions. Geographical dispersion can result in a lack of organization, slow internal communications, and delays in getting decisions. Don’t be shy in following up and asking again if you need information and consider providing a weekly “outstanding items” lists to your client to keep things on track.

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New FDA Guidances for June 2014

By Sheila R. Plant, Ph.D., R.A.C., Regulatory Scientist at Cato Research

FDA draft and final guidances, released from CDER, CBER, and CDRH in June, are posted. Of interest this month, the FDA has provided two new guidances on properly using Internet/social media.  One guidance provides recommendations for advertising on social media platforms with character space limitations, like Twitter, while the other guidance provides recommendations on how to correct third-party misinformation of a prescription product on the Internet, whether it be positive or negative.  Additional guidances on similar topics are found on FDA’s social media guidances webpage:

In addition, upcoming Advisory committee meetings and other public meetings hosted by FDA are listed below with links to more information.

Special Interest Guidances/Information Date Posted
Uncomplicated Gonorrhea: Developing Drugs for Treatment – Draft Guidance 18 Jun 2014
Internet/Social Media Platforms: Correcting Independent Third-Party Misinformation About Prescription Drugs and Medical Devices – Draft Guidance 17 Jun 2014
Internet/Social Media Platforms with Character Space Limitations— Presenting Risk and Benefit Information for Prescription Drugs and Medical Devices – Draft Guidance 17 Jun 2014
Q4B Annex 6: Uniformity of Dosage Units General Chapter – Final Guidance 13 Jun 2014
ANDA Submissions — Content and Format of Abbreviated New Drug Applications – Draft Guidance 11 Jun 2014
Drug Supply Chain Security Act Implementation: Identification of Suspect Product and Notification – Draft Guidance 10 Jun 2014
Providing Submissions in Electronic Format — Postmarketing Safety Reports – Draft Guidance 9 Jun 2014
Distributing Scientific and Medical Publications on Risk Information for Approved Prescription Drugs and Biological Products—Recommended Practices – Draft Guidance 6 Jun 2014
Determining the Need for and Content of Environmental Assessments for Gene Therapies, Vectored Vaccines, and Related Recombinant Viral or Microbial Products – Draft Guidance 20 Jun 2014
Recognition and Use of a Standard for Uniform Blood and Blood Component Container Labels – Final Guidance 5 Jun 2014
Global Unique Device Identification Database (GUDID) -Final Guidance 27 Jun 2014
Criteria for Significant Risk Investigations of Magnetic Resonance Diagnostic Devices – Final Guidance 20 Jun 2014
Medical Device Data Systems, Medical Image Storage Devices, and Medical Image Communications Devices -Draft Guidance 19 Jun 2014
Upcoming Meetings (* = New)
* Public Workshop – The Development of New Antibacterial Products: Charting a Course for the Future; 30-31 July 2014; North Bethesda, MD
* Blood Products Advisory Committee Meeting;31 July 2014; Silver Spring, MD
* Confidentiality of Interim Results in Cardiovascular (CV) Outcomes Safety Trials; Part 15 – Public Hearing Before The Commissioner; Request for Comments; 11 Aug 2014; Silver Spring, MD
* Pulmonary-Allergy Drugs Advisory Committee Meeting; 14 Aug 2014; Silver Spring, MD
* Methodological Considerations in Evaluation of Cancer as an Adverse Outcome Associated With Use of Non-Oncological Drugs and Biological Products in the Postapproval Setting; Public Meeting; Request for Comments; 10-11 Sep 2014; Silver Spring, MD
Joint Meeting of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting; 16 Oct2014, Silver Spring, MD
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Clinical Trials with Chimeric Antigen Receptor T Cells (CAR-T cells)

By: William T. Lee, Ph.D., R.A.C., Vice President of Regulatory Affairs at Cato Research

At the 2014 American Society of Gene and Cell Therapy Annual Meeting (ASGCT) held on May 21-May 24, all the buzz was focused on the astounding results from clinical trials with chimeric antigen receptor T cells (CAR-T cells). These CAR-T cells are the patients’ own immune cells engineered to recognize and attack their tumors. In one clinical trial, 18 of 21 patients with advanced acute lymphoblastic leukemia (ALL) had complete responses.

At least two companies (Novartis and Juno Therapeutics) are developing CAR-T cell technology towards FDA approval as a treatment for ALL. The FDA has been aware of these clinical trials and is anticipating the filing of marketing applications. At this ASGCT meeting, Dr. Dan Takefman, Chief of the Gene Therapy Branch of the FDA, presented the FDA’s view of the manufacturing aspects of CAR-T cells required for release of patient cell lots prior to patient administration.

The critical safety issue of CAR-T cells is that these engineered cells require the use of disabled HIV viral vectors. To ensure that these patients’ engineered cell lots are not contaminated with replication competent HIV viral vectors (called replication competent lentivirus, or RCL), before re-infusion back into the patient, extensive testing is required. This testing is expensive and requires a 4-5 week assay.

Dr. Takefman is encouraging the development of rapid and alternative assays for RCL. But, the big message is that for the FDA to assess safety of CAR-T cell therapy, the FDA needs more data on the safety of the final cell product. Dr. Takefman pointed out that the FDA is encouraged with the safety results obtained to date; FDA has never received a report of an RCL in a patient cell lot. However, the overall experience is still relatively low. Therefore, Dr. Takefman is specifically asking that manufacturers should collaborate to generate data assessing the potential for RCL replication in their cellular product. This combined data should be published, so that FDA can refer to it and better re-assess the current paradigm of testing patient lots.

Can manufacturers collaborate to generate this data? Manufacturers from the gene therapy community have worked together before. In the past, the manufacturers have collaborated on: 1) testing for replication competent retrovirus, 2) generating standards for adenoviral vectors and 3) AAV vectors. On the cusp of such a promising gene/cell therapy, let’s hope that the manufacturers will do so again.


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Toxicokinetic Tips

Richard Stewart Ph.D.; Director, Nonclinical Safety Development; Cato Research

A key component of toxicology studies is the toxicokinetic (TK) assessment. A common question from our Sponsors is, “What’s the difference between pharmacokinetics (PK) and TK?” A straightforward answer is that TK is simply PK performed within a toxicology study. However, a major difference between the two terms is purpose. The primary purpose of the TK assessment is not just to characterize the pharmacokinetic profile of the drug, but rather is to correlate exposure (i.e., maximum plasma concentration [Cmax], and area under the concentration vs. time curve [AUC]) to the toxicities observed in the study. Therefore, the TK profile of a drug is important data that contributes to a better understanding of the overall toxicity profile of the drug, and the more the toxicity profile is characterized in the nonclinical program, the more that safety will be enhanced in the clinical program.

There are a number of distinct steps in the TK process: 1. development and qualification/validation of the bioanalytical method, 2. in-life sample collection in the toxicology study, 3. sample analysis, and 4. TK modeling and reporting.

A common mistake when planning a toxicology program for a new chemical entity (NCE) is to overlook the timing of the bioanalytical method. This method will of course be needed for analyzing the TK samples from the toxicology studies (samples are typically plasma, although other biological matrices may be relevant too, such as serum). However, the bioanalytical method should ideally be in place well in advance of the initiation of dosing in the toxicology studies. Otherwise, the plasma samples may be left sitting frozen while the bioanalytical method is being qualified/validated, and this will necessarily raise questions about the stability of the parent drug (and its metabolites) in the TK samples. This risk can be avoided by finding a facility to develop and qualify (or validate) the bioanalytical method early on in the planning phase of the toxicology program.

Many of the toxicology CRO’s in the marketplace offer bioanalytical services, and if the toxicology studies are placed at a CRO that can also perform the bioanalysis, then this may translate into a more efficient toxicology program, relative to having the TK samples shipped out to an external bioanalytical lab. On the other hand, for some toxicology programs, there may be a distinct upside to placing the bioanalytical work at a specialized bioanalytical lab, such as the need for a novel or complex bioanalytical method.

Once the bioanalytical method is in place, the technical details of the TK assessment will need to be sorted out for each study. CATO believes that a thorough dialogue on the TK design be initiated with the Study Director at the CRO who has been assigned your toxicology study. The TK details that will need to be determined include:

  • Number of whole blood samples: The number of samples should adequately cover the plasma concentration vs. time curve of the drug. If preliminary PK data are already available, then these data will help guide the selection of the TK timepoints. However, if you’re working completely in the dark, then a broad range of timepoints is recommended (e.g., a generic set for an oral drug is: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 12, and 24 h post-dose). The selected timepoints should be frequent enough in the immediate post-dosing phase to capture the Cmax, and importantly, there should be enough timepoints in the terminal phase of the curve to allow for an accurate estimation of elimination half-life (t1/2) and AUCinf.
  • Number of sampling occasions: For subchronic repeat-dose toxicology studies, the rule of thumb is: TK sampling on the first and last day of dosing (e.g., for a 14-day study, Day 1 and 14). Additional sampling occasion(s) may be prudent for chronic studies.
  • Species considerations: TK in rodents is tricky, as mice and rats have a relatively limited total circulating blood volume available for sampling, and therefore separate TK groups are needed in the toxicology study. What you don’t want in your study is oversampling leading to hypovolemia and its accompanying physiologic changes in the animals, which in addition to raising animal welfare concerns, can result in junk TK data. The larger nonrodent species (e.g., Beagle dogs and Cynomolgus monkeys) have a total circulating blood volume that usually allows for extensive serial sampling of each individual animal, provided that the whole blood sample volume is reasonable. Toxicology CRO’s have strict species-specific limitations on the allowable blood sampling volumes, which reiterates the need for frequent and clear communication with the Study Director while the study design is being nailed down (i.e., during draft protocol development).
  • Volume of sample: Aside from the species-specific blood volume limitations noted above, a worthwhile exercise is to work backwards from the volume of plasma needed for the bioanalytical method. For example, if the LC component of your LC-MS/MS method has a 100 µL injection loop, and samples are to be run in duplicate (also, allowing for potential repeat analysis), then a 1 mL whole blood sample would be acceptable, as this volume would yield approximately 400-500 µL of plasma per sample.

Once the TK samples are collected in-life, and plasma prepared and appropriately stored, the next step in the TK process is bioanalysis using the method that was put in place to support the toxicology study. The resulting plasma concentration data will then undergo TK modeling to characterize the TK profile of the drug. For Good Laboratory Practice (GLP)-compliant toxicology studies, it is wise to not initiate the TK modeling of the plasma concentration data until it has been quality assured, as a change in one value may mean a repeat run with the modeling software. In general, noncompartmental TK modeling is adequate for most drugs, and reported parameters are typically Cmax, time to Cmax (Tmax), t1/2, and AUC (note that additional parameters may be appropriate for a given drug, such as clearance [Cl], volume of distribution [Vd], etc.). Other standard elements in the TK modeling report are: determination of the dose-exposure relationship, potential gender differences, and whether there’s accumulation of the drug following repeated administration.

The “pointy end of the spear” for the TK data is their potential impact on clinical safety. The TK profile of an NCE established in the pivotal toxicology studies can be used to guide the selection of safe clinical doses during clinical development. In this way, the animal exposure data can be compared to the human PK data that is generated from the clinical program, rather than comparing animal and human dose levels on a mg/kg or mg/m2 basis. For example, if a severe toxicity and/or non-monitorable toxicity was observed in a pivotal toxicology study, then FDA could limit the human exposure, such as AUC, to the AUC value in the animals where the adverse effect was recorded. Lastly, the nonclinical bioanalytical methods used to support the toxicology program are often useful for setting up the clinical bioanalytical methods – after all, mammals are mammals!

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