Thermodynamic Equivalence: A Revolutionary Approach to Making More Generics Accessible—FDA Agrees to Evaluate PharmSci® Sarfaraz K. Niazi, Ph.D., SI, FRSB, FPAMS, FACB. Executive Chairman, Pharmaceutical Sciences, Inc., 2550 W. Higgins Road, Suite 830, Hoffman Estates, IL 60169 www.pharmsci.com; niazi@pharmsci.com; Where Pharma Meets Science® +1-312-297-0000
Background [Since the FDA allowed my Citizen’s Petition to start considering a new model to allow biowaivers, I have received hundreds of emails inquiring about thermodynamic equivalence testing that I am proposing. This is a brief write up.] The Drug Price Competition and Patent Term Restoration Act (Public Law 98-417)1, informally known as the Hatch-Waxman Act, is a 1984 United States federal law encourages the manufacture of generic drugs by the pharmaceutical industry by establishing the modern system of approving generic drug regulation in the United States. Generic drugs save hundreds of billions of dollars every year2 but recently, the cost savings have begun to erode, requiring a fresh look at the scientific basis of approval of generic drugs. One of the key approval criteria for approving generics drugs is the determination of bioequivalence as codified in in US 21 CFR 320.13 as “the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.” Figure 1 Annual generic drug savings in the US (www.aam.org)
1 https://www.gpo.gov/fdsys/pkg/STATUTE-98/pdf/STATUTE-98-Pg1585.pdf 2 http://www.gphaonline.org/media/wysiwyg/PDF/GPhA_Savings_Report_2015.pdf 3 https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=320.1
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While this statutory definition has been accepted globally by regulatory agencies. However, a basic flaw in the definition of bioequivalence remains intact since the site of drug action is not known in many cases, and even when it is known, the site remains almost impossible to sample the drug concentration. To overcome this statutory compliance issue, the US FDA issued guidance to use pharmacokinetic studies to determine bioequivalence. The justified argument that cause creation of this surrogate test was that once a drug enters the blood, it is safe to assume that the concentration at the site of action will be proportional to concentration in the blood. In using this approach to determined bioequivalence, for example, between two products such as a commercially available brand product with its paten expiring and a potential to-be-marketed generic product, pharmacokinetic studies are conducted whereby each of the preparations are administered in a cross-over study to volunteer subjects, generally healthy individuals but occasionally in patients. Serum/plasma samples are obtained at regular intervals and assayed for parent drug (or occasionally metabolite) concentration. A variety of mathematical parameters such as the area under the plasma concentration-time curve (AUC), peak concentration (Cmax), time to peak concentration (Tmax), and absorption lag time (tlag) are calculated and compared, often at several different doses, especially when the drug displays dose-dependent pharmacokinetics. The classical conventional human pharmacokinetic in vivo bioequivalence study employs a single dose, two period, two treatment, two sequence, open label, randomized crossover design comparing equal doses of the test and reference products
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in fasted, adult, healthy volunteers (e.g. n=24). These studies are an indirect measure of bioequivalence and supposed to represent a study of the drug concentration profile at the site of action4. Figure 2 Pharmacokinetic profiling to prove bioequivalence
Since the enactment of the generics law, millions of subjects have been exposed to drugs during their development in studies that cost millions of dollars and often years to complete. I have been writing on the subject for over four decades, starting with the Textbook of Biopharmaceutics and Clinical Pharmacokinetics5 that was published in 1979 and continues to be reprinted in its original version, as the longest running edition of a technical book. More recently, I have written the largest books on bioequivalence testing, Handbook of
4 https://www.fda.gov/downloads/drugs/guidances/ucm377465.pdf 5 https://www.amazon.com/Textbook-Biopharmaceutics-Clinical-PharmacokineticsSarfaraz/dp/9381075042
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Bioequivalence Testing Second Edition,6 that I dedicated to President Obama as I worked with the WH in developing the details of the AHA that included BPCIA (an act to allow biosimilar drugs to become a reality in the US).
These books are used globally by the industry, as well as the regulatory agencies, in testing drugs and developing guidance for approval of BE testing results. Soon after the FDA promulgated requirements for conducting blood-level studies, suggestions were made to FDA to consider waiting this requirement for certain drugs that are less likely to show differences in their bioequivalence, because of their high solubility and the ease with which they get absorbed in the body. The use of dissolution testing in place of pharmacokinetic studies was allowed for those drugs that dissolve rapidly and where permeability of drug molecules across biological barriers in not problematic. This includes, for example, the drugs that dissolve at least 85% in 15 min (very rapidly dissolving) or in 30 min (rapidly dissolving) or less in pH 1.2, 4.5 and 6.8 dissolution media. These are the drugs where bioequivalence is selfevident making bioequivalence studies redundant. These biowaivers reduced some burden on the generic pharmaceutical industry, yet many challenges remained. [Japan still does not accept biowaivers]. Generally, blood concentration levels are neither feasible or possible to compare the two products (e.g. inhaled corticosteroids), complex dosage forms where a drug is released slowly or in repeated dose, applied to skin or other routes of administration remain subject to bioequivalence testing. Other situations where establishing bioequivalence between two products is required include prototype formulations during early development and pivotal 6 https://www.amazon.com/Handbook-Bioequivalence-Testing-Pharmaceutical-Sciencesebook/dp/B00OKUG3AC
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clinical trial formulations, mapping a process that relates Critical Manufacturing Variables (CMV), including formulation, processes, and equipment variables that can significantly affect drug release from the product, the generic formulation differs from the innovator formulation, as a result of scale-up and post-approval changes (SUPAC changes), implementation of improved manufacturing technologies, scale-up, changes in manufacturing locations, etc. As a result, one of largest cost and time burden and barrier in developing generic drugs remains the pharmacokinetic studies. Since the enactment of the Hatch-Waxman law, in 1984, many scientific advances have been made, many new analytical techniques have been devised and today, we have a much better understanding of how drugs are formulated and tested. The US FDA has always been at the forefront of engaging scientific methods in reducing the testing in line with the US 21 CFR 320.25(a)7 that codifies the universal belief that “No unnecessary human testing should be performed” and goes on to suggest: “The basic principle in an in vivo bioavailability study is that no unnecessary human research should be done.” One reason to avoid testing bioequivalence in healthy subjects is reduce risk to healthy subjects when developing highly toxic drugs or drugs requiring multiple dosing, where toxicity can be increased. Take for example, a highly toxic anticancer drug, which, no matter how it is tested offers a peculiar dilemma when tested in healthy subjects as well as in patients. There remained is a dire need to re-evaluate the scientific rationale behind the current methods of testing bioequivalence with aim to reduce or eliminate human testing where possible. I spent several years developing a scientific approach that will be suitable for the risktaking by the regulatory agencies, while providing cost and time advantage to developers and safety for test subjects.
A New Approach to Bioequivalence (BE) Testing In creating a new approach to conduct BE testing, we examine the differences between two drug products by testing them across a biological barrier that adds large inherent variability to 7 https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=320.25
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observed differences. Take for example, in Figure 3 and Table 1, the actual difference (series 1) between two products is confounded by added variability (series 2-4). Figure 3 Compounded variability involved in pharmacokinetic studies to evaluate bioequivalence
Total Difference 140 120 100 80 60 40 20 0 Generic Series1
Innovator Series2
Series3
Series4
Table 1 Additive variability factors
Generic Innovator Source Series 1 15 10 inherent 2 20 20 dissolution 3 30 30 absorption 4 50 50 disposition Total 115 110 variability Statistically, it would be easier to determine a 50% difference (10 and 15, Table 1, Series 1) than a less than 5% difference (110 and 115, Table 1); yet this is how choose to test this difference by using bioequivalence studies. To cost of using this approach comes in using a larger population selected on a statistical basis based on two considerations; a type 1 error, meaning finding a product equivalent when it is not—and that is limited only to 5% and a type 2 error, meaning finding a product not non-equivalent when it is equivalent and that is often placed at 80%; the former error is for FDA to assure safety and the latter error is the manufacturers risk. In some cases where the variability is large, we end up enrolling hundreds of subjects to determine the inherent difference.
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A logical method of testing differences between two products should be based on the ability of the products to release absorbable drug molecules at the site of administration, as the movement of drug molecules beyond this point will be identical, the human body is agnostic to how a molecule got there. The release of drugs from a dosage form is tested by the dissolution rate of the drug product and the FDA has established detailed guidance on how to test dissolution rates of drugs that are subject to bioequivalence variability8 and the US Pharmacopoeia provides details of required dissolution testing for over 1500 products.9 Generally, this approach to testing drug products would be able to pick out any differences in the bioequivalence but it does not always work, for a scientific reason, that has long been ignored in the scientific arena. To understand the reasons why bioequivalence is not always predicted by dissolution rate, we need to invoke principles of thermodynamics in modifying the dissolution testing. The transport of drug molecules across biological barriers from the site of administration is dependent on the chemical potential or activity, not the concentration of drug at the site of delivery. The chemical potential is the concentration of molecules free to move across the biological barrier. Chemical potential of molecules at the site of administration depends on the strength of inter- and intra-molecular bonding in the dosage form that can vary for a variety of reasons, from differences in the active and inactive excipients and method of manufacture. Dissolution of a drug product is a function of the cumulative inter- and intramolecular bonding and the current dissolution testing conditions, which are mostly created to simulate a physiologic environment, provide high force or energy that readily overcomes the energy of inter- and intra-molecular bonding obviating study of any differences. Figure 4 describes to products TS1 and TS2 with different thermodynamic barrier. For a highly soluble drug, the barrier Delta G is small, overcoming any differences between two products. If the energy applied is above the energy required by TS2 then both products will show similar behavior. Figure 4 Thermodynamic energy potential of two products
8 https://www.fda.gov/downloads/Drugs/Guidances/UCM456594.pdf https://www.accessdata.fda.gov/scripts/cder/dissolution/ 9 http://www.usp.org/resources/dissolution-methods-database
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The current dissolution methods use dissolution media, temperature, additives and other conditions to dissolution substantial quantity of active drug from a drug product; the media include most popularly, simulated gastric fluid, simulated intestinal fluid, with or without addition of surfactants, and buffers, mostly at 39oC. Thermodynamic equivalence of drug products is established from dissolution profile under conditions wherein any clinically meaningful differences in the thermodynamic energy of two products can be differentiated. One way to do is to reduce the rate of dissolution as this reduces the energy put into testing and thus does not readily break the stronger bonds. Table 2 lists conditions that are useful in making the dissolution testing a thermodynamic tool. Table 2 Modification to dissolution methods to test thermodynamic equivalence
Condition
Impact
Temperature
Reducing temperature to just above the freezing point of the medium will provide the best conditions to differentiate dosage forms.
Polarity of medium
A polarity opposite to the polarity of drug substances reduces dissolution rate, such as using an organic medium for water soluble drugs.
pH
Significant changes in dissolution can be achieved by altering the pH of ionizable drugs
Physical agitation
Reducing agitation increases dissolution times
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Additives
Using additives that have an opposite impact than what are used for currently in enhancing dissolution.
A practical approach will involve creating dissolution profiles at conditions that provide clearly different dissolution profiles, at least three and then matching these profiles between the two products compared. Multiple conditions, such as a lower temperature and different polarity, agitation or additives can create a large matrix of dissolution profiles for comparison. It is important to remember that the purpose of this exercise is not to simulate any physiologic condition as currently practiced but to provide stress conditions capable of differentiating inter- and intra-molecular bonding that can be clinically meaningful. Another novel approach to testing intra- and inter-molecular bonding differences is in the melt profile of a solid product (Figure 5). The technique is widely used to show differences in the complex character of biological drugs. A dosage form can be subject to melt profiling and then testing how well the two products are superimposable. Figure 5 Melt profile of a biological product to show differences in bonding forces
It was after years of similar discussion that the FDA agreed to consider the concept of TE that can be continually used to assure life-cycle therapeutic equivalence. The FDA has now opened this discussion agreeing that the concept needs to be explored further10. The action was taken
10 https://www.regulations.gov/comment?D=FDA-2007-P-0055-0004
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by the head of CDA CDER (Center for Drug Evaluation and Research and conveyed to me in a letter by Dr. Janet Woodcock11
Quality Impact
A significant application of the proposed approach comes in being able to use this method for all types of products, complex, multiple-release, sustained release, and all dosage forms, oral, topical, rectal, vaginal, etc. However, a large quality impact comes in using this comparison periodically to assure that a generic product remains comparable to the originator product, an aspect of quality that is not currently invoked by regulatory agencies because of the difficulties in conducting clinical testing.
Summary
In summary, there are several concrete reasons for challenging the current methodology of testing bioequivalence. The pharmacokinetic profile of a drug product does not constitute a good surrogate for the concentration of drug at the site of action; this is mostly presumptuous. The ultimate test of bioequivalence should be the rate and extent of delivery of drug at the site of administration, not the site of action. The potential for a drug to be absorbed in the biological system is proportional to the chemical potential of the drug at the site of administration, which is in turn proportional to the thermodynamic potential or energy of the drug product. The thermodynamic potential of drug products can be measured by subjecting them to conditions wherein the dissolution profiles are altered or studying melt profile of the compared products; observing similar changes between the test and the reference drug product should establish thermodynamic equivalence. The thermodynamic equivalence can be applied to every type of dosage form regardless of its release characteristics since the test establishes that under all conditions the chemical potential will be identical to the innovator product or a reference product. The thermodynamic potential test can be used as a routine test to monitor the quality of the product throughout the lifetime of the product. There is no 11 http://www.prnewswire.com/news-releases/pharmaceutical-scientist-inc-fda-calls-forpublic-comments-on-bioequivalence-testing-300489368.html?tc=eml_cleartime
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rationale for exposing healthy humans to drug testing when the results show that these data are inconclusive. Significant cost savings and reduction in the development time can be achieved by eliminating all human testing. The use of thermodynamic equivalence will eliminate the exposure to humans, reduce the cost of development and allow faster regulatory approvals--all needed to bring the cost of drugs on a global basis.
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