Beyond Filgrastim —The Story Untold – Express Pharma Pulse

Beyond Filgrastim —The Story Untold

The Filgrastim row ended up in the fall-out of a cluster of questions which are critically significant. But it hardly yields any answer, observes S Harachand

IT was nearly a month ago that Nicholas Piramal India Limited moved Monopolies Restrictive Trade Practices Commission (MRTPC) alleging that the product inserts of Dr Reddy’s Grastim is a mere duplication of Roche’s Filgrastim injection – Neupogen. Neupogen is being marketed in India by Nicholas Piramal (NPIL). Following the directive from MRTPC, Dr Reddy’s Laboratories (DRL) has made an apology and effected necessary changes in the product insert (PI).

Again NPIL approached the trade disputes redressal forum and Drug Controller General of India (DCGI). This time with a more serious plea: the drug (Grastim) should either prove its clinical efficacy and safety profiles or else be withdrawn from the market.

Grastim is available in all major cities for some time now. And hundreds of vials have already been prescribed. NPIL reasons its arguments on two major counts. Firstly, on the difference in the molecular and physical features between Neupogen and its biogeneric Grastim. Secondly, and more importantly about the safety and clinical efficacy of a possible untested biotech drug.

Is Grastim Filgrastim?

Grastim’s product literature shows it is ‘Filgrastim Injection’. As per the existing guidelines, any drug substance claiming therapeutic equivalence has to demonstrate comparability to the already approved and marketed product. It should be pharmacologically similar to the original or the innovative product.

‘‘Filgrastim is a composite of 175 amino acids. The sequence of these amino acids in Grastim presented in Dr Reddy’s brochure indicates it is different in a few places from that of Neupogen’s Filgrastim. And the physical characterestics of both like molecular weight, retention time too are found to be varying,’’ explains Dr G L Telang, managing director, Roche Scientific Company (India) Pvt Ltd, Mumbai.

So, is it possible for a specific molecule to have dissimilar properties? In one of the statements issued by the Basel-based F Hoffmann-La Roche, which holds the worldwide rights of Neupogen, says ‘‘any other protein with a different amino acid sequence and molecular weight cannot be called Filgrastim.’’ Then what’s Grastim? ‘‘That Dr Reddy’s has to answer. It may even be Filgrastim.. but it needs to be proved,’’ opines Dr Telang.

Filgrastim belongs to a class of therapeutics called granulocyte colony stimulating factor or G-CSF. Right now there is one more G-CSF available in the market – Lenograstim (Granocyte) from Rhone-Poulenc Rorer (now Aventis).

‘‘But Lenograstim’s indications are different,’’ says Sangita Topiwala, manager, Scientific Services and Regulatory Affairs, Roche Scientific Company, India. A change in the molecular features, even a very minor one, can alter the chemistry of the drug substance, she adds.

According to her, efficacy and tolerability of therapeutics have to be demonstrated through extensive pharmacokinetic and pharmacodynamic (PK/PD) studies in applied indications. If Grastim claims same efficacy profiles as Filgrastim they have to support it atleast with PK/PD data. International guidelines on drug equivalence also specifies that drug products are considered to be therapeutic equivalents only if they are pharmaceutical equivalents.

On Purity & Safety

Electrophoresis studies conducted in NPIL’s Quest Institute of Life Sciences (QUIL), Mumbai, reveal the existence of ‘‘an extra minor band’’ in the Grastim samples. ‘‘When tested against Neupogen, samples of Grastim shows an additional band. It can be impurity or drug aggregate. We can’t comment on its nature without detailed analysis,’’ maintained Dr Bansilal, who conducted the studies.

A molecular biologist based in Mumbai said purity is of paramount importance in biopharmaceuticals. Especially in proteins produced through recombinant technology in E coli bacterium. Impurities can be many things including bacteria. The bacteria escaped through purification process can bring in potential hazards to the patients. For instance, a slight change in the manufacturing process of Salk polio vaccine caused some people to contract the disease in the 1950s.

Impurities lead to antibody formation or immunogenicity. It is an important property distinguishing most biologics from small drug molecules (chemicals). Antibody formation can alter the bioavailability of the substance. This narrows the therapeutic

International guidelines on drug equivalence also specifies that drug products are considered to be therapeutic equivalents only if they are pharmaceutical equivalents

window of the compound and may raise the potential for toxicity, he explained.

Director and chief scientific officer of NPIL, Dr Swati A Piramal said the company has alerted all leading haematology and oncology associations in the country, following the findings. ‘‘This is the first time in NPIL’s history we are putting up a court case. It’s not about patents or trade marks. Not about MNCs versus Indian companies. But it’s a battle for safe and effective drugs for the patients…To ensure that doctors are not misled and get correct information from pharma companies. And we feel it’s our duty to fight it to the finish.’’ Neupogen’s is a small, say around 10 crore, market in India, she clarified.

Dr Piramal said NPIL has also pleaded with the regulatory bodies to see that children and the critically ill are not given untested drugs, ‘‘See, these [biotech] drugs are not like vaccines. We administer vaccines in healthy people. But we inject drugs into patients who are weak with disease and failing… Get the drugs tested abroad if facilities are not available in India than injecting them straight into the innocent children.’’

Dr Reddy’s should come out with corrective advertisements to quell the misinformation, upholding the tradition of good ethical practices followed by leading companies like Warner-Lambert etc, once they realised they went wrong, she added.

Paucity of Counter-info & Ensuing Confusion

As the headlines on Nicholas-DRL fight continued to figure in the media week after week, it assumed the shape of a controversy resulting in some some sort of confusion among the sections of medical community.

Most doctors depend upon the product literature for drug information, especially for new molecules. ‘‘Since there is no mechanism to furnish us with the info regarding new drug approvals and other details we mostly rely on product leaflets to learn about the recommended indications and adverse reactions. We make prescriptions according to it. If you go on changing it, omitting or deleting this critical bit of information, off and on, it can only create confusion,’’ reveals a leading oncologist with Tata Memorial Hospital in Mumbai.

He argues that cost-effective

drugs are drugs of choice in our country. It is a welcome move on the part of reputed companies like Dr Reddy’s to come out with affordable versions of costlier and speciality biologicals. At the same time, the companies or the approving authorities are obliged to come forward with some reasonable explanations to allay the fears in doctors and even in patients, in such situations. If there occurs a negative eventuality, the prescribing doctors can be the first casualty, then.

It is true that the MRTPC or DCGI has directed DRL to remove the objectionable reference from the Grastim product literature. However, the approving authorities remained uncomfortably silent on the clinical behaviour of the drug and its safety. Neither the scientists from Recombinant Committee for Genetic Manipulation (RCGM) of the Department of Biotechnology (DBT) nor Genetic Engineering Approval Committee (GEAC) under the Ministry of Environment responded to the queries on possible efficacy and safety if, if at all, it (Grastim) turns out to be a different molecule as NPIL claims.

Sources from DCGI’s office said DRL has been given approval for G-CSF and not specifically for Filgrastim. ‘‘As of now DCGI does not have the required sophisticated facility to test a biogeneric molecule and assess the various parameters. We grant approval based on the data presented by the pharma companies as well as the clearance given by DBT and GEAC,’’ said a senior official with DCGI.

The formalities of clinical trials and the data are first presented to RCGM and they are supposed to recommend to DCGI on granting market authorisation. But one RCGM scientist contended the responsibility of clinical trials are under DCGI and RCGM is to do the toxicity and animal allergenicity studies inorder to give the environmental clearance. One senior scientist with RCGM who did not want to be quoted said: ‘‘A biotech product through any other route cannot really have exactly the same properties. In Grastim’s case the clearance given was only for G-CSF.’’ Clarifying that any change in the protein sequence can surely mean change in chemical and physical properties of biotech product, the official said they are now working on a draft policy on bioethics and will be circulated soon.

Wheareas, DRL continued to maintain that NPIL’s allegation are totally baseless and misleading. ‘‘Along with our drug license application we had submitted our draft label, which identified the drug as Filgrastim. Filgrastim is the international non-proprietary name of recombinant human Granulocyte Colony Stimulating Factor produced in E.coli. We believe that none of the parameters raised by NPIL on the difference between Grastim and Neupogen has actually been tested before making the allegations,’’ officials from DRL said.

They said DRL is getting good feedback from various cities on the efficacy profile of Grastim. However, DRL did not find it important to justify its claim or counter-allege NPIL’s offensive with the sort of scientific data NPIL has come forth with. They went on modifying product inserts (PIs) as per regulators directives, instead.

Biologicals: Regulators’ Nightmare?

Biogenerics market is a high value, high return, technology intensive superspeciality. Globally, market value for recombinant proteins is estimated to be $14 billion and is expected to reach $25 billion by 2005. Biotech related patents are rarely clear cut and the potential entrants will have to fight expensive legal battles, observed Dr Jayaram Chigurupati, vice-president (Emerging Businesses), DRL, in one of his presentations in July this year. An ABN-AMRO study appeared in July this year also finds generic biologics as the next frontier.

Over the next few years, a number of first generation biopharmaceuticals will come off-patent or lose marketing exclusivity. Unlike drugs made of purified small molecules, biopharmaceuticals are difficult to characterise chemically. Proof of comparability for a biogeneric made by another manufacturer too is more difficult. Therefore ‘‘it is challenging, both in scientific and regulatory terms, to determine if these drugs are comparable and therapeutically equivalent when made by different companies,’’ cites one report from

The report says there are no clear, specific regulations established for dealing with generic biopharmaceuticals. Without these, it is unclear whether a generic biopharmaceutical market will be allowed to exist. In the US, the Complex Substances Coordinating Committee (CDS CC) has been assigned with the task. Meanwhile in Europe, the Committee for Proprietary Medicinal Products (CPMP) is providing the guidance. They also suggest there can be no ‘‘universal guidelines’’ and each product has to be reviewed on a case to case basis.

As this is the scenario in leading global markets, it cannot be an easy job for Indian regulatory bodies to think of better

Nicholas-DRL row spotlights one question which is profoundly important: Who’s accountable for the safety in public health? The drug providers or the health providers or the watchdog authorities?

biogeneric laws for a drug market which is basically generic-depended, and is likely to continue to be so at least for the next few years. Further, more and more companies here are poised to enter into the prospective biogeneric business.

Authorities, therefore, have to see to it that regulations on biogenerics are going to be clear at the same time making sure that it is not posing any entry-barriers for the industry.

A smooth regulatory process in India calls for efficient infrastructure and better co-ordination between the different departments right now assigned with the task. Since it involves potential hazards pertaining public health and environment, the drug approval process needs to be independent and fool-proof — not relying much on the data presented by the manufacturers.

Whatever maybe the motive, the Nicholas-DRL row spotlights one question which is profoundly important: Who’s accountable for the safety in public health? The drug providers or the health providers or the watchdog authorities? Medical practitioners cannot but look towards companies for drug information, as there is no other source. And the latter means business, of course.

If DCGI’s words are anything to go by, the proposed expert committee to probe the NPIL-DRL issue are purported to consider ‘‘the complex underlying issues’’ than limiting itself to settle the dispute or framing some laws demanding more extensive clinical data for biogeneric approval. As an expert put it, they can even go one step further outsourcing the required data in case of new molecules, if need be, other than continue managing to say ‘‘we are in the learning process’’ in matters involving human life.

(Jayashree Padmini/New Delhi contributed to this article.)