Me-Too Drugs - A Tiny Revolutionize

Vikash Kumar

What are “Me-Too” Drugs? ^{1, 2} : The Process of new drug development is complicated, time-consuming and expensive.

In modern chemotherapy, when drugs were discovered and developed through the process of screening thousands of molecules for a variety of disease conditions, using animal models, there has been a growing criticism that too many molecules were developed with similar chemical structure and the same pharmacological profile, with very little to distinguish them from each other in terms of their therapeutic utility.

In other words, once the first breakthrough discovery is made of a new pharmacological activity for a new molecule, subsequent years saw the emergence of a host of new molecules or "me-too" drugs from the same chemical class and possessing the same pharmacological profile.

A drug that is structurally very similar to already known drugs, with only minor differences is called as Me-too drugs. Several examples can illustrate this phenomenon: propranolol was followed by atenolol, metoprolol, esmolol, labetalol, timolol, carvedilol, etc.; Cimetidine followed by rantidine, fmotidine, nizatidine and others; sumatriptan was followed by narratriptan, almotriptan, rizatriptan, zolmitriptan, etc; Losartan followed by candesartan, valsartan, telmisartan, etc. Many other examples can be given; ACE inhibitors, proton pump inhibitors, calcium channel blockers, etc.

Such “me-too” have been termed molecular modifications, follow-up drugs, molecular roulettes or copycats, the developments of which are alleged to be motivated by purely commercial considerations. They are also deemed to involve lower levels of innovation, compared to the original molecule. It is important to analyze in a historical perspective the end results of such efforts in different therapeutic areas of developing new molecular entities, as later generation products, after an initial breakthrough discovery has been made and the technical, medical and commercial merits of developing such drugs.

History of "Me-Too” drugs¹ :

US President Franklin Roosevelt’s only son, Franklin Delano Jr. had a bad case of tonsillitis and with fever soaring, the White House physician George Tobey Jr. feared the worst. The infection had seeped into the blood, which in those days was a potentially fatal condition. Tobey gave the president’s son a new German drug called Pronosil.

To Tobey’s surprise, young Roosevelt ’s fever quickly subsided. A few days later the press heralded both the medicine and the miraculous recovery in the first family. “New control for infection”, The New York Times headlined its front-page story. The era of wonder drugs was underway.

Prontosil was discovery by Gerhard Domagk, a young physician on the staff of Bayer Laboratory in Elberfeld, Germany. A husband and wife team in France soon discovered that it was not the dye that killed the streptococci, but one of its constituent, which only became active after the patient metabolized the original drug. The active ingredient in Prontosil, they discovered was sulphanilamide, a common industrial chemical that was no longer patented and that no one had ever thought to test against bacteria.

Within month, every drug company in the world began synthesized their own version of sulphanilamide. As war clouds gathered over Europe, England, France, Germany and United states began pedding their own version of the miracle sulfa drug. These first copycat drugs, usually called me-too drugs by industry insider.

Development of "Me-Too” Drugs^{2, 3, 5, 15} :

The success rate in the discovery of new chemical entities with fundamentally new chemical and biological profiles of activity is very low. In fact, even chemical entities within the same structural class of an approved drug are becoming rare now, compared to the period of sixties to eighties. In 2001, $26 billion was spent on developing new drugs and only 9 new chemical entities were approved by the U. S. FDA. At the same time, two thirds of the drugs approved from 1989 to 2000 were modified versions of existing drugs or even identical to those, in newer forms and formulations.

The FDA classified 53 percent of the drugs approved between 1982 and 1991 as offering "little or no therapeutic gain." Of the 1,035 drugs approved by FDA during 1989 to 2000, only 361 or 35% contained new active ingredients. Between 1996 and 2001, things got worse: The pharmaceutical companies’ were spending on research and development increased by 40 percent, but the number of new drugs reaching the market decreased by 50 percent.

Table 1 Analysis of me-too drugs on WHO’s essential drug list¹⁵

* Drugs and indications meeting criteria for inclusion

Of 31 "blockbuster" drugs (those with annual sales of $1 billion or more) launched between 1992 and 2001, 23 were me-too drugs for common conditions such as allergies and inflammation. From 1998 through 2003, 487 drugs were approved by the US Food and Drug Administration (FDA). Of those, 379 (78%) were classified by the agency as "appearing to have therapeutic qualities similar to those of one or more already marketed drugs," and 333 (68%) weren't even new compounds (what the FDA calls "new molecular entities"), but instead were new formulationsor combinations of old ones. Only 67 (14%) of the 487 were actuallynew compounds considered likely to be improvements over olderdrugs.

Rationale for “Me-Too” Drugs²:

Notwithstanding such perceptions, historically, many "me-too" drugs have proved to be considerably better than their original counterparts. Examples are a series of generations of beta-blockers, which came up after the original drug Propanolol was discovered by ICI, with most of them having merits in terms of better efficacy, cardio-selectivity and safety. It is perhaps questionable whether each of the over two dozen beta-blockers in the market has unique properties to warrant their preferred usage over the earlier ones. Ranitidine, the first follow-up drug after the introduction of the first H₂ receptor antagonist, Cimetidine, was followed by Famotidine and in each case these "me-too" drugs had notable merits over the original drug.

Apart from the major breakthrough in the development of orally active beta lactam antibiotics of the Penicillin and Cephalosporin class, within the same oral derivatives, there have been considerable improvements brought about by change in the side chains. A whole new range of broad-spectrum antibiotics of these structural classes could thus be developed. In each of the major classes of antibiotics, classified according to the mechanisms of their action, namely inhibition of cell wall synthesis (Beta Lactams, Vancomycin), inhibition of bacterial protein synthesis (Erythromycin, Tetracycline, Streptomycin), inhibitors of DNA or RNA replication (Quinolones, Rifamycins), inhibition of Folate Coenzyme biosynthesis (Sulfa drugs, Trimethoprim), there have been several "me-too" drugs marketed.

In the area of Serotonin uptake inhibitors, used as Antidepressants, it has been noted that apart from the success of Fluoxetine, newer products of the same class, such as Paroxetine were better suited for both efficacy and tolerability in many individual patients. In fact, particularly in the case of CNS drugs, for reasons, which are not clear, patients who do not respond to one drug, get benefited by another drug of the same class. The case of Non-Steroidal Anti-inflammatory Drugs (NSAIDS) is no different. They differ a great deal with respect to efficacy and patient tolerance; in fact, in many cases, an agent useful for a particular patient, is selected after trying the various available drugs, even of the same class.

Lovastatin (Mevacor), Simvastatin (Zocor), Pravastatin (Pravachor) and Atorvastatin (Lipitor) are all members of the sam e HMG Co-A reductase inhibitor family of cholesterol reducing drugs. Mevacor was FDA approved and released in U.S. in September 1987, Pravachol in October 1991 and Zocor in December 1991. All three are successful drugs on their own merit. An important recent example to show that 'me-too" drugs need to be developed is the case of the oral hypoglycemic drug Troglitazone., approved as an anti-diabetic drug in 1997. The drug was withdrawn from the market following reports of unacceptable hepato-toxicity. The "me-too" drugs, Rosiglitazone and Pioglitazone are much less toxic and are today widely used. If these drugs were not developed, the withdrawal of Troglitazone would have left a major therapeutic gap in anti-diabetic therapy.

First generation anti-histamines were of short duration (requiring multiple-dosing), produced sedation and had severe anti-cholinergic effects, properties, which are considerably reduced in second and third generate on products. For example, Terphenadine (Seldane) has been replaced by its faster acting metabolite Fexofenadine (Allegra). Among the Calcium Channel Blockers, the first drug, Verapamil is still used in treating arrhythmias, while the newer one, Nifedepine is a selective dilator of the peripheral smooth muscle. With Diltiazem, the effect is in between, balancing its effect on heart as well as the peripheral vascular system.

Patenting of “Me-Too Drugs” ⁶ :

Besides the fact that since most new “me-too” drugs are much more expensive than equally effective older drugs, they represent a waste of health care resources, the above development also explains why the MNCs are pushing aggressively for patents to be granted on me-too drugs. If patents are not allowed for me-too drugs (which are also marketed aggressively as a replacement to the older drug for which patents are expiring), then these companies will lose their market monopoly.

If these drugs are not “novel” but are just new use/form/modification of existing drugs and it is obvious from the approvals above that this is the case, then patents should not be granted for these drugs. In short these drugs should be excluded from patentability altogether.

India, which has a thriving generic industry has taken this route and disallowed patenting of new uses. The provision in their patent law is as follows: “the mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process, machine or apparatus unless such known process results in a new product or employs at least one new reactant. Explanation.—for the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pure form, particle size, isomers, and mixtures of isomers, complexes, combinations and other derivatives of known substance shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy”.

Benefits of “Me-Too” Drugs^{4, 9, 12, 13} :

The primary benefit of what DiMasi and Paquette⁷ label “me-too” drugs is the increased therapeutic choice they present. Some “me-too” drugs are better than the pioneer drug for most patients, while others are better for a substantial fraction of patients. The increased choice between drugs can be very valuable, particularly for patients for whom the pioneer drug is ineffective or entails undesirable side effects⁸. In addition, for some classes of drugs, such as antibiotics, having more drugs can help to protect against resistance (Calfee, 2000). DiMasi and Paquette observe that around 33% of the me-too drugs they identify received a priority rating from the FDA, indicating that there was considerable expectation that the follow-on drugs would likely create some significant therapeutic benefit. Of course, to the extent that new drugs do confer significant benefits, they are less likely to meet the suggested definition of me-too drugs.

The second major benefit from me-too drugs is that they would be valuable if they led to substantial price reductions, although in practice price competition between therapeutically similar drugs does not tend to lead to significant price reductions. Lu and Comanor (1998) using American data, and Ekelund and Persson (2003) using Swedish data, have shown that drugs categorized by the FDA as having “little or no therapeutic gain” are typically introduced at around the same price as existing therapies in the US and at about twice the price of existing therapies in Sweden¹⁴. Lu and Comanor calculate the effect of entry on prices and find that the average effect of adding an extra competitor is a price reduction on the order of 2%. (The average number of competitors in their data is approximately 3 or 4, which seems to suggest that the effect of going from pure monopoly to four firms with very similar products is a reduction in price of only 6 %). Other data from very large drug markets shows how the entry of me-too drugs may not work according to the standard expectations. Cockburn and Anis (1998) examine pricing of anti-arthritic pain-relievers before the Cox-2 inhibitors Celebrex and Vioxx entered. Their regressions of price on therapeutic quality show exactly the “wrong” relationships: efficacy is negatively correlated with price, while toxicity is positively correlated. They do at least find that market shares go in the “right” direction. Azoulay (2002) shows that in the H2 stomach ulcer market, Tagamet’s price increased when its first competitor Zantac entered, rather than going down. Prices for both drugs continued to increase when new competitors (Pepcid and Axid) entered. Such strange results from pharmaceutical markets are not intended to show that price has no effect on sales in pharmaceutical markets, but that me-too drugs very frequently not only fail to increase price competition but may even lead to price increases. In summary, the evidence on price competition from me-too drugs suggests that it confers little benefit to consumers.

References:

1. Khan, N. S., “Me-too drugs” what are they and are they necessary, Trendz; Vol. 8, Issue-I, July-Sept. 2005.

2.Nair, M. D., Rationale for chemically modified ‘me-too drugs’, Wednesday, Pharmabiz; March 05, 2003.

3.Marcia Angell, “Excess in the pharmaceutical industry”, Canadian Medical Association Journal, December 7, 2004; 171(12) 1451.

4.Aidan Hollis, “Me-too drug: is there a problem?” Department of economics, University of Calgary , December 13, 2004.

5. Peter Lansbury, “washingtonpost .com: An Innovative Drug Industry? Well, No”, Sunday, Nov. 16, 2003; p. B02.

6. Sangeeta Shashikant, TWN Info Service on Intellectual Property Issues, 12 Sept 2006.( http://www.twnside.org.sg/title2/intellectual_property/info.service/twn.... .090604. htm )

7. DiMasi J and C Paquette, 2004, “The Economics of Follow-on Drug Research and Development Trends in Entry Rates and the Timing of Development.” Pharmacoeconomics 22 (Suppl. 2): 1-14.

8. Marcia Angell, The truth about the drug companies. New York : Random House, 2004; p. 90.

9. Azoulay. P., “Do Pharmaceutical Sales Respond to Scientific Evidence?” Journal of Economics & Management Strategy, 2002, 11(4): 551-594.

10. Calfee, J. E., 2000, Prices, Markets, and the Pharmaceutical Revolution, Washington DC: American Enterprise Institute Press.

11.Ekelund Mats and Björn Persson, 2003, “Pharmaceutical Pricing in a Regulated Market.” Review of Economics and Statistics 85(2): 298-306.

12. Lu, Z. J., and W. S. Comanor, 1998, “Strategic Pricing of New pharmaceuticals.” Review of Economics and Statistics 80(1): 108-118.

13. Cockburn I, Anis AH, 1998, “Hedonic Analysis of Arthritis Drugs.” NBER Working, Paper 6574.

14. Lichtenberg, F. R., 2004, “Pharmaceutical Knowledge-Capital Accumulation and Longevity.” In Carol Corrado, ohn Haltiwanger and Daniel Sichel, Editors, Measuring Capital in a New Economy. Chicago : University of Chicago Press.

15. Wastila, Linda, J. J. Clin. Res. Drug Dev. 3: 105–115, 1989.

About Authors:

Vikash Kumar
SBMN Institute of Pharmaceutical Sciences & Research, Asthal Bohar, Rohtak
E-mail: vikasruhilo1@yahoo.co.in, vikasruhil01@rediffmail.com

Balvinder Singh
SBMN Institute of Pharmaceutical Sciences & Research, Asthal Bohar, Rohtak