The discovery and development process of the Tamiflu
The Discovery and Development Process of the Tamiflu (R)
Every drug has its own life story that covers its entire journey from conception of an agent as a drug to its final use by a patient. This process is governed by extremely rigorous guidelines. Tamiflu or its generic form Oseltamivir is an anti viral drug used for treatment of and prophylaxis against Influenza A and B has had its own share of controversies and triumphs. It was hailed as a solution to the threat of influenza pandemic but its efficacy and safety profile is now being debated raising questions about the process of approval. Intellectual property and patent concerns also have to be addressed.
Keywords: Tamiflu, Oseltamivir, Influenza, Pandemic.
The drugs that are used to treat various ailments are approved after a rigorous evaluation process. The entire process of development of a drug encompasses many stages and it is only a select few that make the cut. This paper will focus on these stages with special emphasis on Tamiflu. The discussion will cover the drug’s structure, mechanism of action, side effects, optimum dosage and the various questions that are being raised about the drug’s efficacy and the results of post marketing surveillance. Patent laws that govern drugs like Tamiflu will also be discussed.
STEPS INVOLVED IN DRUG DEVELOPMENT AND APPROVAL (Spilker, 2000).
Preclinical phase- an agent is identified by scientists as having the potential to act as a drug on basis of its structural or chemical properties.
Wait! The discovery and development process of the Tamiflu paper is just an example!
Animal testing- Once an agent is taken up by a company as a potential drug it undergoes animal testing to test for any major side effects and confirm its mechanism of action.
INVESTIGATIONAL NEW DRUG APPLICATION (IND)-
Depending on the results obtained after animal testing, the manufacturing company compiles all the data related to the preclinical phase, testing phase and future trials and submits it to the regulating authority in form of an IND (Spilker, 2000).
The next step involves clinical trials which take place in various phases. These trails are usually approved and supervised by a local review board consisting of a group of scientists and they decide the basic protocol and methodology of the trial. All the tests are conducted after obtaining informed consent from the volunteers.
Phase 1- this phase is executed on healthy volunteers ranging from 20-80 in number.
The basic purpose of this phase is to find out the most common adverse effects and study the process of drug metabolism and excretion.
Phase 2- This phase is executed on around 100- 300 people who have an illness on which the effect of the drug has to be studied. The various dosing parameters and the best route of drug administration are studied. The primary focus of this phase is on evaluating the effectiveness of the drug.
Phase 3- The drug is studied in various doses in different ethnic groups and populations in around 100-3000 volunteers.
Finally, a new drug application (NDA) is submitted to the regulatory body with details of all the data related to manufacturing, trial phases and pharmacology of the drug.
Phase 4 or post marketing surveillance- Involves continuous monitoring of the drug’s performance once it is available for use commercially (Finnegan and George 19).
Medical personnel have an opportunity to notify the regulatory authorities of any adverse effects caused by the drug.
This phase also involves study of all adverse effects that may develop due to repeated or chronic use of a drug and continuous collection and evaluation of data that can help in optimizing the dose of the drug.
CLASS AND STRUCTURE OF TAMIFLU:
Tamiflu is the trade name of drug Oseltamivir phosphate. It is a member of the family of gamma amino acids and derivatives and is an aliphatic homomonocyclic compound with a chemical formula of C16 H22 N2 O4. (Kamps and Hoffman 195).
Figure 2: Structure of Tamiflu (Kamps and Hoffman 195)
PHARMACOLOGY AND MECHANISM OF ACTION
This drug is administered orally for the treatment of uncomplicated Influenza A and B with the duration of the illness less than 48 hours. The drug can be used only in children with age greater than one year. In adults and adolescents greater than 13 years of age it can be used as a prophylactic drug.
In the oral form it is a prodrug in ethyl ester form and is converted to its active form GS4071 which is its carboxylate ester once it is acted upon by hepatic esterase enzyme (Davies ii8).
This carboxylase form is a competitive inhibitor of viral neuraminidase enzyme. The carboxylate form has a side chain which is lipophilic in nature and binds to neuraminidase thus interfering with the production of new virions.
The drug absorption is minimally affected by food. Its oral bioavailability ranges from 75-80% and it has a half life of 1-3 hours. Renal excretion is the primary mode of excretion and the drug is excreted in its carboxy form.
DOSAGE AND SIDE EFFECTS:
According to CDC( Centre for Disease Control and Prevention), American academy of Pediatrics, European Centre for Disease Control(ECDC) Tamiflu should only be used in influenza illness in people who belong to high risk groups like persons at extremes of age, suffering from any co morbidity, pregnant women . For healthy people the scientific community has been unable to reach a consensus with some like the CDC advocating its use within the first 48 hours of the illness whereas others advising against it (Holzinger et al. 363) The broad consensus is that the use of the drug should be balanced against its side effect profile .
THE RECOMMENDED DOSAGES FOR TAMIFLU ARE:
In case of use in adults and adolescents in the age group more than 13 years the drug is given in a dose of 75 mg twice a day for 5 days.
In younger children the drug is prescribed twice a day for 5 days according to weight of the child as shown below:
< 15 kg- 30 mg
16- 23 kg- 45 mg
24-40 kg-60 mg
> 40 kg- 75 mg
The dose of the drug for influenza prophylaxis is 75 mg once a day for 7 days.
SIDE EFFECTS OF TAMIFLU:
Nausea, vomiting, diarrhea, abdominal discomfort, otitis media, and asthma were most common in the pediatric age group. Adults demonstrated side effects like headache, renal problems, mood disturbances and cardiac disturbances. Post marketing surveillance has demonstrated various other side effects like increased levels of hepatic enzymes, inflammation in the liver, anaphylaxis, toxic epidermal necrolysis, Steven Johnson Syndrome, seizures, hemorrhagic colitis and uncontrolled diabetes. It is a category C drug in pregnancy in the United States and category B in Australia thus implying that it has been used by a small number of pregnant women with no report of any major adverse effect (Nelson and Holmes 205).
ISSUES REGARDING DRUG APPROVAL AND POST MARKETING SURVEILLANCE:
Tamiflu or its generic form Oseltamivir was extracted by researchers at Gilead Sciences from shikimic acid which was derived from Chinese star anise (Karpf and Tussardi 2045) Then with development of recombinant technology using E.coli a better method was devised for manufacturing the drug. Hoffman-La Roche was able to secure the patent for manufacturing this drug.
According to the company trials showed results in favor of the drug by concluding that the use of Tamiflu decreased the severity of symptoms associated with Influenza, reduced the duration of stay in the hospital and also reduced number of deaths. In the year 2000 a study was published in the Journal of the American Medical Association stating that a Randomized Controlled Trial conducted on the drug concluded that there was 30% reduction in the duration of the disease and 40% reduction in the complications when Tamiflu was used within 36 hours of occurrence of the first symptom. Lancet also published a study in 2000 and showed agreement with the above findings. FDA approval was granted to Tamiflu in 1999.
A systematic review sponsored by the World Health Organization took place under Jonathan et al .and the findings of this review also echoed the results mentioned before.
During the H1N1 pandemic 09 Roche conducted a study whose findings again trumpeted the benefits of Oseltamivir.
As a result of all these findings the EMA (European Medicine Authority) granted approval to Oseltamivir in 2002. On escalation of avail influenza epidemic governments stocked up on Tamiflu as a means of preparedness to contain the epidemic.
As a result Roche reaped huge profits from the sale of this drug. It is estimated that profits of the scale of 18 billion dollars were produced by Tamiflu.
CONFLICT OF INTEREST AND EFFECT OF MARKET DYNAMICS:
The post marketing phase has raised certain important queries regarding the effectiveness and safety profile of Tamiflu.
The drug was used quite widely in Japan and many cases of psychiatric problems and mood disturbances were noticed after using Tamiflu especially in the pediatric age group. This forced the manufacturers to include a warning on the package and include the information pertaining to these side effects in the package insert. The query was raised as to why these side effects were not mentioned in all the studies that were cited by Roche and used by the FDA and EMA to grant approval to the drug.
In the year 2006, Cochrane collaboration took into account the confusion produced in the scientific community by Tamiflu and conducted a review which concluded that there was no significant effect produced by Tamiflu on the illness caused by seasonal influenza virus (Ebell et al 133, Jefferson et al.361).
This is where the question of conflict of interest and market dynamics arises. Whenever a manufacturer shows faith in a compound which it hopes will ultimately become a profitable drug it usually sets up trials and since the trials are sponsored by the company itself there seems to be a bias inherent in such a setting that gives results in favor of the drug in question.
But, it can be said that both the FDA and EMA are independent bodies which would have taken decisions based solely on the effectiveness of Tamiflu. A thorough review of the process of approval of Tamiflu showed that though the FDA and EMA granted approval and recommended Tamiflu they did not take into consideration the quality of data put forward to them. Queries put forward by Cochrane have shown that Roche did not publish some part of the data related to phase 3 of Tamiflu’s trials. It also claims that data regarding side effects like cardiac arrhythmias, prolongation of Qtc interval, mood disturbances, suicidal tendencies, convulsions, encephalitis were deliberately not released. According to Cochrane a difference of magnitude of 1.06% was discovered by two trials conducted on Tamiflu using two separate doses of the drug 75 mg and 150 mg in relation to side effects related with nervous system with a P value of .038.
There were also flaws in the Randomized Control Trials which were used as the basis of granting approval by the FDA. These trials were riddled with flawed study designs, bias, confounding factors. Since the data obtained from the trials and study was of a low quality according to Cochrane the role of FDA came under the scanner. Since, an influenza epidemic was raising its ugly head and there was no other drug on the market which claimed to alleviate symptoms related to the disease and due to public sentiment the FDA’s judgment was clouded. In an effort to reduce the indiscriminate use of the drug and curb its aggressive marketing The FDA issued a warning to Roche in 2000 against misleading advertisement.
This case study demonstrates that despite many checks and balances that are an inherent part of the drug development and approval process there are times when market dynamics, unethical business practices, public sentiment and prevalent health related issues can lead to overriding of these checks.
A review released by Cochrane in 2014 has refuted the claims of the manufacturer and concluded that Tamiflu does not appear to have any significant effect on the severity of the disease by pooling together results and analysis of 46 trials related to this class of drug. According to Cochrane the presumed effects of decreasing the complications associated with influenza as shown in various studies were not true as these studies had flawed design and there were no definite criteria to study the severity of the complications. It went one step further and postulated that their findings showed that Tamiflu blunted the immune response in certain patients and reduced their ability to fight against infection. Cochrane urged the medical and scientific community to look into the recommended guidelines of Tamiflu’s use. However, the CDC, and ECDC along with the American Academy of Pediatrics and Roche have raised objections against Cochrane’s conclusions and no change in previous recommendations has occurred to date.
The next section incorporates some tables with data related to the efficacy of Tamiflu.
INCIDENCE OF INFLUENZA AND INFLUENZA – LIKE ILLNESS IN THE OSELTAMIVIR AND PLACEBO GROUPS*
OR ILLNESS OSELTAMIVIR PLACEBO
(N=520) TWICE DAILY
(N=520) COMBINED GROUPS
(N=1040) Culture-proved influenza-like illness – no. of subjects (%) 0 4 (0.8) 4 (0.4) 15 (2.9)
Protective efficacy — % (95% CI) 100† 73 (29 to 93) 87 (65 to 96) P value <0.001 0.011 <0.001 Laboratory-confirmed influenza with fever »37.8°C – no. of subjects (%) 2 (0.4) 5 (1.0) 7 (0.7) 19 (3.7)
Protective efficacy — % (95% CI) 90 (61 to 98) 74 (37 to 91) 82 (60 to 93) P value <0.001 0.004 <0.001 Laboratory-confirmed infection (symptomatic Or asymptomatic) – no. of subjects (%) 28 (5.4) 27 (5.2) 55 (5.3) 55 (10.6)
Protective efficacy — % (95% CI) 49 (24 to 69) 51 (26 to 70) 50 (31 to 67) P value 0.002 0.001 <0.001 Influenza-like illness without laboratory evidence of infection – no. of subjects (%) 5 (1.0) 6 (1.2) 11 (1.1) 7 (1.3)
Protective efficacy — % (95% CI) 29 (¡83 to 87) 15 (¡108 to 84) 22 (¡67 to 83) P value 0.58 0.79 *P values are for the comparison with placebo. CI denotes confidence interval.
†The 95 percent confidence interval could not be estimated. (Hayden, FrederickG et,al 1999)
INCIDENCE OF LABORATORY – CONFIRMED INFLUENZA – LIKE ILLNESS IN THE OSELTAMIVIR AND PLACEBO GROUPS *
VARIABLE OSELTAMIVIR PLACEBO
GROUPS All sites
No. of subjects 520 520 1040 519
Laboratory-confirmed clinical influenza – no. of subjects (%) 6 (1.2) 7 (1.3) 13 (1.3) 25 (4.8)
Protective efficacy — % (95% CI) 76 (46 to 91) 72 (40 to 89) 74 (53 to 88) P value <0.001 0.001 <0.001 Virginia
No. of subjects 268 267 535 268
Laboratory-confirmed clinical influenza – no. of subjects (%) 3 (1.1) 4 (1.5) 7 (1.3) 19 (7.1)
Protective efficacy — % (95% CI) 84 (53 to 96) 79 (45 to 94) 82 (60 to 93) P value 0.004 0.006 <0.001 Texas and Kansas
No. of subjects 252 253 505 251
Laboratory-confirmed clinical influenza – no. of subjects (%) 3 (1.2) 3 (1.2) 6 (1.2) 6 (2.4)
Protective efficacy — % (95% CI) 50 (¡55 to 94) 50 (¡54 to 94) 50 (¡23 to 93) P value 0.49 0.47 0.39 *Protective efficacy was estimated as the rate of laboratory-confirmed influenza-like illness among subjects assigned to once-daily or twice-daily active drug, divided by the rate among subjects assigned to placebo; the result was subtracted from 1 and expressed as a percentage. P values are for the comparison with the placebo group and were calculated with Fisher’s exact test (adjusted by the bootstrap method for the primary end point). CI denotes confidence interval.
(Hayde,Frederick G.et al,1999)
Table 3: Protective efficacy of Tamiflu (Hayden,Frederick G, et al 2004).
ISSUES RELATED TO INTELLECTUAL PROPERTY AND PATENT:
As discussed earlier Gilead Sciences base in the United States discovered Oseltamivir which is the generic form of the drug Tamiflu and handed over the rights of manufacturing, licensing, sales and distribution to Roche which is a Swiss pharmaceutical company. The original patent of the drug is still with Gilead and will expire in the year 2016. The patent and rights of Roche do not cover the entire world; there are certain countries like Thailand, Philippines and Indonesia which do not recognize these rights. However, not much progress has been made in such countries regarding the manufacturing of a drug similar to Tamiflu probably due to financial and logistic constraints. An Indian Company Cipla has manufactured a drug called Antiflu.
The most important issue regarding patent related to Tamiflu arises because it is feared that if a pandemic occurs then the availability of the drug solely in the hands of a single company can not only lead to skewed demand supply situation but also may lead to escalating prices and black marketing.
All these factors were discussed and lawmakers came up with the provision of “Breaking the Patent” details of which were laid down in Article 31 of the agreement put forward by the World Trade Organization under the Trade Related Aspects of Intellectual Property Rights (TRIPS). In case of Tamiflu this implies that in an emergency a government can allow any company to manufacture the drug even though Roche has the rights of manufacturing. In such a situation, Roche can continue to manufacture and sell its own product and will be compensated by the government authorities with the amount deemed fit for the losses it may incur in such a situation. It is also important to remember that in such a scenario, the government authorized license would be for one particular drug whereas the original patent as in case of Gilead and Roche would cover a broad variety of drug like the entire class of neuraminidase inhibitors.
Roche also has the authority to grant sub license to other manufacturing companies so that they can manufacture Tamiflu. It has granted such licenses to Shanghai pharmaceutical group in China and the Hetero Drugs in India.
It is important that lawmakers are aware of the patent issues related to Tamiflu and provision of TRIPS so that in case of a pandemic the drug is not merely available to a select few countries or class of people .
All the phases of drug development and approval are of the utmost importance in ensuring that a safe and effective drug reaches the general public. The case of Tamiflu reflects the importance of these phases and also places emphasis on the need for more vigilance, consistency and safeguards in the drug development and approval systems so that no conflicting information clouds the real effectiveness of the drug. Patent and intellectual property issues should also be kept in mind while dealing with drugs that might be needed for emergency purposes. It is the responsibility of all the people involved in this process to make sure that standards set up by regulatory authorities are adhered to so that new and safe drugs can be developed in a positive environment and help save millions of lives.
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Davies, BE. Pharmacokinetics of oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations. The Journal of antimicrobial chemotherapy. 2010. Print.
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