With over one dozen of India's top pharmaceutical companies venturing into new drugs research, the question is often raised as to what would be the preferred R&D strategies for Indian companies to adopt. Such clarity is important in view of the limited resources available, as well as the competition from the leading R&D-based companies the world over, notably in U.S.A., Western Europe and Japan. The options available include those that rely on discovering and developing follow-up molecules of existing drugs and drugs under development, all of them patent protected. Such an approach is generally termed the "me-too" approach for new drug discovery.
What Are "Me-Too" Drugs?
Ever since the advent of 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.
Such follow-up drugs have been termed molecular modifications, molecular roulettes or copycats, the development 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 analyse 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.
Development Of "Me-Too" Drugs
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.
Of the 1,035 drugs approved by FDA during 1989 to 2000, only 361 or 35% contained new active ingredients. Of these, only fewer than half were granted priority review status by the FDA, indicating that the rest were not significantly relevant to therapy and the delay in their approvals will not affect medical care.
Opinions vary regarding the compulsions, which lead to development of "me-too" drugs. One impression is that these drugs are slightly altered versions of existing drugs, with little to offer in terms of better activity or tolerance, let alone new pharmacological profiles. The implication is that such drugs are developed, as patents on top-selling original drugs run out and not many truly new medicines are discovered. The indication that many of these drugs do not offer any major advantages over existing drugs is given by FDA's unwillingness to grant priority review for most of them.
On the other hand, conventionally, the Regulatory Agencies, including the FDA, are not obliged to consider better efficacy over existing drugs as a criterion for approval; rather, they require only the establishment of efficacy and safety of the new drug over a placebo.
Rationale for "Me-Too"Drugs
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 Propanalol 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 have unique properties to warrant their preferred usage over the earlier ones. Ranitidine, the first follow-up drug after the introduction of the first H-2 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 incorporated by condensation of specific agents with 6-APA, 7-ADCA and 7-ACA. 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.
Even though the major problem of antibiotic therapy, namely drug resistance cannot be addressed by the development of "me-too" drugs, due to the propensity of the same class to develop cross resistance; in most cases, the new semi-synthetic derivatives had distinct advantages over the earlier ones. Thus, for example, the first generation Cephalosporins are useful for gram-positive infections, while the second-generation drugs cover a broader spectrum including gram-negative organisms. The third generation drugs provide resistance against the beta lactamase enzyme, as well as acting against some of the most intractable infections, such as those caused by Pseudomonas and Klebsiella strains.
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 same HMG Co A reductase inhibitor family of Cholesterol reducing drugs. Mevacor was FDAapproved 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. The last of the series, Lipitor is the leading product in this class today. The drugs developed based on the first drug, Lovastatin, constitute follow-up drugs, which to some extent cashed on the success of the latter drug in the market place.
Whether such success in the market is entirely due to the merits of the individual drugs or due to marketing strategies and inputs has been debated. With "me-too" drugs, yet another differentiator, assuming that they are more or less equal in other parameters, is their pricing. However, since the later generation drugs enjoy longer patent protection, compared to the original one, they are generally more expensive. The recent trends, particularly in the U.S., where prescription drugs are advertised in the lay print and visual media, have added yet another dimension by creating a market pull for individual drugs, through patient participation in influencing the prescription patterns followed by physicians.
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 follow-up "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 generation 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 arrythmias, while the newer one, Nifedepine is aselective 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.
Role of Patents In Drug Discovery
Patents provide the best incentives for Pharmaceutical Companies to invest in R&D for discovery of new drugs.By and large, the patent system has been responsible for the industry to be what it is today. However, even this system does not always ensure adequate returns on investments made in R&D. Insufficient returns on investments can happen under many scenarios. For example the new drug's performance in the market place may not reach expected levelss, better dugs may be introduced by competition, the drug may come out with unexpected side-effects forcing its withdrawal or banning of the drug, and the period of validity of the patent may be inadequate to recoup the investments made. For example, approximately, 11 years could elapse between the filing of the patent and the introduction of the drug, due to the long development times required, thereby reducing the effective patent life to 9 years.
As the patent runs out, the Generic products, copies of the innovative drug, enter the market with prices reduced to almost 50% or more in the first year itself. With innovations being fewer in the Industry for a variety of reasons, more Patents are expiring than being generated. Already during the last two years the generic market in volume terms have increased to 50% of the prescription drug market. It is therefore logical that "me-too" drugs regardless of how close they are to the original molecule still have to have strong patent protection if investments in their developments are to be justified.There are instances where the patentability of the new drug over the claims on the original molecule has been questioned leading to infringement suits and litigations.
Strategies for New Drug Research for Indian Companies
Breakthrough innovations in pharmaceutical industry, of new drugs, such as the first beta blocker, the first NSAID, the first of each class of Antibiotics, Calcium Channel blockers, ACE inhibitors, Sulfonyl Ureas, Biguanides, Insulin, Glitazones, Glinides, Tricyclic Anti Depressants,major and minor Traquillisers, Selective Serotonin Receptor inhibitors, H-1 and H-2 Receptor antagonists, Proton Pump inhibitors etc are relatively rare and even though a few of the original drugs under these classes are still very much in use, they have been superceded in most cases, by later generation products, many of them "me-too". The newer drugs are discovered both through incremental innovations on the original drugs as well as through new research.
Generally the original discovery leads to feverish activity both within the innovator company as well as in Competitors' laboratories, to develop better products in the same therapeutic category. The essential caveat for commercial success, however, is that the newly discovered molecules should meet the minimum standards of patentability. For example within three years of the discovery of the highly successful Sildinafil Citrate (Viagra), three more new versions for the same indications have been patented and developed.
Traditionally, new drugs have been discovered based on knowledge derived from activity of Natural Products, through random screening oflarge numbers of synthetic molecules, or by chance or serendipity. Even though recent rational methods using Combinatorial Libraries, Molecular Targets and High Throughput Screening are likely to lead to better and more specific and tailor made drugs for specific diseases and individual patients, the costs of new candidate molecule discovery is unlikely to be lower.The capital investments and technical and scientific skills required for success are also substantial. Indian R&D Centres, both publicly and privately funded by Government and Industry respectively, have rightly adopted the strategy to follow the leads already available from marketed drugs, or products in the pipe-line, and discover drugs through molecular modifications. The examples of Dr. Reddy's Glitazones and other molecules from other laboratories, which have reached the IND status with the Drug Regulatory Agencies bear testimony to this approach.
A necessary pre-requisite, however, to justify this approach, and ensure its success, would be that the improved products should be patentable, which in turn emphasizes the need for Companies to be increasingly Patent savvy, not only with respect to analyzing the Patent Portfolios of the innovator Companies, but also to ensure that they develop internal strengths to create their own Patent Portfolios. Through this approach, the leading R&D based Indian Companies will be able to discover new drugs and develop them in-house or in collaboration with international companies through the licensing route.
-- The author is one of India's leading research scientists