Therapeutic Dose: Life-Cycle Management: A Veritable Hydra

Should improved process control or safety measures extend a product's patent exclusivity?

By Emil W. Ciurczak, Contributing Editor

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In preparation for an upcoming workshop, I have been brushing up on the concept of Life Cycle Management (LCM) of pharmaceutical products. The concept is not new in either pharma or “normal” manufacturing. Brand names from soaps to computers to motor oils have always been updated and labeled “new and improved.” (Although, if something has been improved, it isn’t truly new, just changed and, if new, it is original and couldn’t have been improved. But I digress.) In many cases of consumer products, new products are simply introduced to replace the old ones: the 386 computer chip was replaced by a 486, the 486 by a Pentium (when it was discovered you couldn’t copyright a number), and so forth.

However, the situation is a bit different for drug products, which are bound by a more stringent set of rules. Anyone may introduce a new soap, perfume, or electronic gadget and the sales will be driven by market demand. With a drug substance, many, many more tests need to be performed to ensure safety and efficacy than a consumer widget. The time and cost of development of a new drug substance is quite a bit more than for most other products. In addition, there needs to be both a medical condition to treat and proper physiological activity on the part of the new chemical entity to make a product. It is not surprising, then, that pharmaceutical manufacturers want to keep their products on the market as long as possible.

This, however, is the point at which opinions begin to differ on the means and reasons behind Life Cycle Management. Whenever a company reformulates a proprietary product, it comes with the suspicion that it is merely an attempt to block generic competition. There are a number of cases being looked at by the Federal Trade Commission as to whether such activity raises anti-trust questions. Of course, we have to examine the entire concept of LCM from several points of view.

Let’s assume that research shows that an extended release dosage form is advantageous to the original formulation. This could be true for various reasons: a dose could be missed if it is to be taken every four hours, there is a chance for an overdose with an immediate release form, better control of blood levels, and several others come to mind. In these cases, the originating company indeed deserves an extension of its exclusivity. But, who actually decides what is “significantly better” than the original formulation and what is a stalling tactic?

Who decides what is better than the original formulation and what is a stalling tactic?

A great example of improved is any allergy medicine that lasts twelve hours or more; no one wants to start sneezing at 2 AM. An example of public safety would be the reformulated Oxycontin that makes it more difficult for drug abusers to extract the active. Indeed, there are any number of healthcare reasons for reformulation and the protection afforded that new product.

Another reason, often unspoken, is on the regulatory side: one manufacturer of a product is far easier to police than multiple generic companies scattered throughout the world. Every drug product that is legally produced by multiple sources (i.e., the originating manufacturer and generic companies) adds to the burden of the FDA, EMEA, and other agencies worldwide. Even if the thought is subconscious, the agencies would prefer an extension of current products than to contend with more and more inspections.

Also never mentioned is “national interest.” One has to ask, “What is the impact to, say, a U.K. company’s employees when their biggest seller is produced in India and China?” It is a rule of thumb that any drug challenged by a generic brand will drop by (at least) 50 percent. While the income of the particular company is most often discussed, the need for the manufacturing employees also drops concomitantly.

Another head of the Hydra would be the definition of “reformulation” under Quality by Design. One part of QbD (that drives QA people crazy) is that “every batch is a validation batch.” Small changes, based on differing properties of incoming raw materials and processing variations, are constantly being made. Manufacturers are being urged to evolve their products to better and better states of control. After a few years of improved control, assume the variation of a product’s drug substance has dropped from + 6% to + 2%. Does this constitute a “new or improved” product? Better yet, with better control, the “process signature” of a product has become more and more constant; doesn’t this aid in anti-counterfeiting efforts? It may well be argued that this effort should be rewarded an extension of patent/exclusivity rights. Whilst the “reformulation” is not directly an “improvement” (although better side-effect and dosage levels may be inferred from more precise dosing from better controlled API), it aids the overall public health.

The Life Cycle Management picture is not, after all, so clear, and I hope to address more facets of LCM in upcoming columns.

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