Orphan drugs

Drugs used for rare disease

1. Orphan Drugs Presenter:- Dr Arun Singh 2 nd Year PG Student Department of Pharmacology SMS Medical College,Jaipur

2. Outliners 1.Definition 2.Criteria 3.Rare Diseases 4.Essential Drugs Vs Orphan Drugs 5.Orphan Drug Act’1983 6.Examples of drugs and Manufacturers 7.Orphan drug designation process 8.Indian Perspective 9.Conclusion 10.References

3. Definition The so-called 'orphan drugs' are intended to treat diseases so rare that sponsors are reluctant to develop them under usual marketing conditions. The process from the discovery of a new molecule to its marketing is long (10 years in average), expensive (several tens of millions of euros) and very uncertain (among ten molecules tested, only one may have a therapeutic effect). Developing a drug intended to treat a rare disease does not allow the recovery of the capital invested for its research.

4. Orphan drugs may be defined as drugs that are not developed by the pharmaceutical industry for economic reasons, but which respond to public health need. Actually, the indications of a drug may also be considered as ' orphan ' since a substance may be used in the treatment of a frequent disease but may not have been developed for another, more rare indication.

5. Criteria The FDA Orphan Drug Designation is granted to medicines and biologics that are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases or disorders which is one that affects less than 200,000 persons in the United States. Or In the  European Union   (EU), the  European Medicines Agency  (EMA) defined a drug as "orphan" if it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically and seriously debilitating condition affecting not more up to 10,000 EU people.

6. Rare Disease A rare disease occurs infrequently in a population, but there is no universal definition. The three elements to the definition as used in various countries are as follows: 1. The total number of people having the disease 2. Its prevalence 3. Non-availability of treatment for the disorder

7. Country Total population affected, less than 1 per Prevalence per 10000 of population USA 200,000 7.5 JAPAN 50,000 4 SOUTH KOREA 20,000 4 AUSTRALIA 2,000 1.1 TAIWAN 10,000 1 EUROPE - 5 China 50,000 - India ☺ ☺

8. India, like many developing countries, currently has no standard definition. Considering the large population of India, ORDI (Organization for Rare Diseases in India) suggests a disease to be defined as rare if it affects 1 in 5,000 people or less. The World Health Organization (W.H.O.) has suggested that a rare disease should be defined as one with frequency less than 6.5 – 10 per 10,000 people.

9. Populations based frequency of rare disease (According to CIOMS) Sr. No. Rare Disease Frequency Total Populations 1. Very Common >/=1/10(>/=10%) 2. Common,Frequent >/=1/100 and <1/10(>/=1% and <10%) 3. Uncommon,Infrequent >/=1/1000 and <1/100(>/=0.1% and <1%) 4. Rare >/=1/10000 and <1/10000(>/=0.01% and <0.1%) 5. Very Rare <1/10000(<0.01%) CIOMS: Council for International Organizations of Medical Sciences.

10. Brief About Rare Disease There are more than 7000+ Rare Diseases known/reported world-wide. Over 350 Million people world-wide are affected ~30 Million in USA, ~30 Million in EU, ~70 Million in India. About 80% of RDs are genetic in origin many of them being monogenic. Only ~500 approved orphan drugs exist in the market and over one hundred in clinical trials.

11. Majority of the diseases have no treatment and when they exist, are mostly unaffordable. Early diagnosis is a critical challenge in RD management (Avg. time: 5-7 years) Affordability While nearly all genetic diseases are rare diseases, not all rare diseases are genetic diseases. There are also very rare forms of infectious diseases, such as auto-immune diseases and rare cancers. To date, the cause remains unknown for many rare diseases.

12. Rare diseases are serious, often chronic and progressive diseases. For many rare diseases, signs may be observed at birth or in childhood, as is the case of proximal spinal muscular atrophy, neurofibromatosis, osteogenesis imperfecta, chondrodysplasia or Rett syndrome. However, over 50% of rare diseases appear during adulthood, such as Huntington diseases, Crohn disease, Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis, Kaposi's sarcoma or thyroid cancer.

13. Distinction between Essential medicines and Orphan drugs Aspects Essential Medicines Orphan Drugs Concrete policies in place since : 1977 worldwide 1983 in USA, 2000 in EU Primary focus : Public health : bringing effective medicines to as many patients as possible Individual patient : even a single patient warrants Initiated and developed by : WHO, and Member States Governments of Australia, EU, Japan, and USA; patient groups Criteria : Drug driven (i.e. drug to be listed on EML is efficacious, safe, cost-effective, based on evidence based data, etc.) Disease driven (i.e. disease to be classified as an orphan drug has low prevalence < 5-7.5 : 10000, is life-threatening, etc.) Policies aim to : Provide established medicines to patients Provide new medicines to as yet untreatable patients Target populations : Initially low-income countries, now all countries High-income countries, developed countries Economics : Cost-effectiveness, sustainable and affordable access Relatively high prices per individual patient, cost-maximization per population

14. Features of orphan drug incentive systems in the USA and EU Feature USA EU Program established 1983 – the Orphan Drug Act modified the Federal Food, Drug and Cosmetic Act 2000 – Orphan, Medicinal Products Regulation Prevalence criterion for rare disease < 200 000 patients in the USA (< 7.5 : 10 000) Life-threatening or chronically debilitating disorder that affects <5: 1000O in the EU Requirements for orphan drug designation Rare disease, or research and development costs cannot be recovered in 7 years Rare disease, or product unlikely to be developed without incentives or new product will be of significant benefit Products eligible for orphan drug designation Drugs and biologicals (including vaccines and in-vivo diagnostics) Dugs and biologicals (including vaccines and in-vivo diagnostics) Market exclusivity 7 years; prevents same product being approved for the same indication unless clinical superiority is shown 10 years; can be reduced to 6 years if orphan drug criteria no longer met Other benefits Regulatory fee waivers, 50% tax credit on clinical research after designation; grants for clinical research (pharmaceutical companies and academia eligible); protocol assistance; faster review if indication warrants; research grants for medical devices and medical food. Regulatory fees can be reduced or waived; access to centralized procedure; protocol assistance. Individual Member States have to implement measures to stimulate the development of orphan medicinal products

15. Orphan drug Acts,1984 USA became the first country to enact Orphan Drug Act on January 4th,1983. The law is designed to facilitate the development and commercialization of drugs to treat rare diseases, The salient features of the act are as follows: i. Incentives to Pharma companies investing in Orphan Drugs R&D ii. Faster/Priority clearance of Orphan Drugs Application through FDA iii. Market exclusivity for 7 years for Pharma companies to recover costs

16. Global Statistics of Orphan Drugs As of 2014, there were 281 marketed orphan drugs and more than 400 orphan-designated drugs in clinical trials. More than 60% of orphan drugs were biologics. The U.S. dominated development of orphan drugs, with more than 300 in clinical trials, followed by Europe.  Cancer treatment was the indication in more than 30% of orphan drug trials. Number of orphan drugs in clinical trials: 600 Number of orphan drugs in Phase-2 Trial: 231 Number of orphan drugs in U.S. clinical trials: 350 in the pipeline from research until registration

17. Companies involved in the manufacture of orphan drugs 1. Celegene 11.Amgen 2.Johnson & Johnson 12.Jiangsu Hengrui Medicine 3.Roche 13.Astra Zeneca 4.Novartis 14.BioMarin Pharmaceutical 5.Takeda 15.Biogen 6.Abbevie 16.Incyte 7.Sanofi 17.Bristol-Myers Squibb 8.Vertex Pharmaceuticals 18.Eisai 9.Alexion Pharmaceuticals 19.CSL 10.Pfizer 20.Syros Pharmaceuticals

18. Few examples of orphan drugs and it’s market’s player Drug Pharmaceutical Companies Therapeutic Indication 1. Eloctate  Bioverativ, a Sanofi Company Acute Haemophilia-A 2. Hemin (Brand name: Panhematin Abbott Laboratories Acute intermittent porphyria (AIP)  3. Octreotide (Brand name: Sandostatin LAR) Novartis Pharmaceuticals Acromegaly 4. Edaravone (Brand name: Radicava) Mitsubishi Tanabe Pharma Corporation Amyotrophic lateral sclerosis (ALS). 5. Porfimer sodium (Brand name: Photofri  Pinnacle Biologics Inc  Barrett's esophagus  6. Mifepristone (Brand name: Korlym)  Corcept Therapeutics, Inc Cushing's syndrome  7. Infliximab (Brand name: Remicade) Centocor, Inc Crohn's disease  8. Deflazacort (Brand name: Emflaza) PTC Therapeutics Duchenne muscular dystrophy (DMD) 9.I matinib mesylate (Brand name: Gleevec®) Novartis Pharmaceuticals  Gastrointestinal stromal tumor (GIST)

19. Drug Pharmaceutical Companies Therapeutic Indication 10. Rifaximin (Brand name: Normix Salix Pharmaceuticals Hepatic encephalopathy  11. Paclitaxel (Brand name: Taxol) Bristol-Myers Squibb Co HIV/AIDS 12. Amphotericin B Liposomal (Brand name: AmBisome®)  Astellas Pharma US, Inc  Leishmaniasis 13. Eculizumab (Brand name: Soliris) Alexion Pharmaceuticals, Inc  Myasthenia Gravis 14. laronidase (Brand name: Aldurazyme BioMarin Pharmaceutical, Inc. Mucopolysaccharidosis I (MPS I)  15. Risdiplam (Brand name: Evrysdi) Genentech  Spinal muscular atrophy (SMA) 16. Fosphenytoin (Brand name: Cerebyx®) Pfizer Status epilepticus

20. Orphan Drug Designation Process Sponsors have to first send request to the Office of Orphan Products Development (OOPD) to grant orphan designation to their drug or biological product to take advantage of financial incentives available for further product development. And then send NDA (New Drug Application) to the Centre for Drug Evaluation and Research (CDER) or the Centre for Biologics Evaluation and Research (CBER) to market their orphan drug or biological product.

21. After Submission of Designation Process Request Typical review cycle ~ 90 days (often less) Will either receive: -Designation Letter Or -Deficiency Letter Once designated, sponsor is required to submit annual reports until drug is approved

22. Review of a Designation Request involves- 1.What is the disease/condition? 2.Is the disease rare (prevalence)? 3.Is there sufficient scientific rationale that demonstrates “promise” that the drug/biologic will treat, diagnose or prevent the disease/condition at issue?

23. Indian Perspective Coming to the Indian scenario, so far, ~450 rare diseases have been identified in India. It was statistically estimated that, in India, the rare disease and disorder population was 72,611,605 as per published data of national population census of 2011. Now, the awareness for rare disease is increasing. Scenarios for many rare diseases are also changing. Cystic fibrosis was thought to be very rare in India, but genetic analysis has now shown that the disease is prevalent but was undiagnosed earlier.

24. India has reportedly higher rare diseases population than the world average, but initiatives from government side are still less, and in fact, India lacks national legislation for orphan medicines and rare diseases, in spite that these are most populated countries. The first attempt to bring together all experts of rare disease under a common platform was initiated by INSA, which conducted the first of the kind rare disease workshop entitled “To Develop a Scientific Program for Research on Rare Diseases” in 2016, which deliberated on issues such as definition of “Rare disease,” rare disease awareness, rare disease research avenues, policy framework for boosting and incentivizing research and  development (R and D) efforts, and framing suitable legislation to ensure involvement of the State in fulfilling the special needs of rare diseases.

25. Dr. APJ Abdul Kalam addressing the issues of rare disease said, “a coordinated effort at the national level is the need  of the hour for more research and understanding rare diseases in the country. There is a need for a whole ecosystem consisting of doctors, a registry to record the prevalence of rare diseases, biobanks, support groups, more research on drug discovery, and of course, a regulatory framework. Each component is complex, and there is a lot of work ahead.”

26. Financial incentives available to orphan drug developers in India Currently, drug developers in India are receiving no formal incentives from the Government and hence they are more focused on -developing affordable drugs for more common diseases such as oral insulin -statins for preventing or slowing the progression of cardiovascular disease -vaccines and antibiotics for a number of preventable infectious diseases, etc. Hence, patients with rare diseases in India have to rely on imported drugs from western countries which makes these treatments (even when available) unaffordable.

27. Financial assistance to rare disease patients in India The healthcare system in India is mostly self-funded by the patients. This restricts the affordability threshold for drugs and diagnostic tests to around 25 thousand rupees (~400- 500 USD) per instance or about a lac rupee (~1600- 2000 USD) per year on recurring expenses for most patients. The costs of most available orphan drugs are significantly higher than this affordability range requiring the need for financial assistance.

28. Patients look for patient foundations, other nongovernmental organizations, and charitable access programs offered by certain Pharma companies to cover these costs. Examples of such initiations are: -Birth Defects Registry of India(BDRI) -Lysosomal Storage Disorders Support Society -Metabolic Errors and Rare Diseases organization -Association for Social and Health Advancement -Haemophilia Foundation

29. -Sjogren’s India -Pompe Foundation o Muscular Dystrophy Foundation -Alzheimer and Related Disorders Society Of India -Rett Syndrome Foundation o Association of Persons with Rare Eye Diseases -Amrithavarshini -ABLE (Association of Biotechnology Led Enterprises) -Mumbai Marathon

30. Biggest hurdles to improving patient access to orphan drugs in India Awareness among doctors, patients and other stakeholders of rare diseases, relevant clinical trials and orphan drugs. Affordability and Accessibility (easy import and distribution) of orphan drugs in India. Enactment of the Orphan Drug Act by the Government of India. Without assurance of marketing exclusivity, IP rights and other financial incentives, the orphan drugs industry is unlikely to succeed in India

31. Conclusion The new approved orphan drugs should be easily accessible and affordable to patients with rare diseases in India. Government of India and the other Pharma/Biotech/Diagnostic industry should work together to enact an Orphan Drugs Act (ODA) and that will create incentives for orphan drug developers. Government needs to create a framework that is conducive to enabling the manufacturing of orphan drugs in India.

32. Summary 1.The drug which are used for rare disease is called orphan drugs. 2. These drugs are not developed by the pharmaceutical industry for economic reasons, but which respond to public health need. 3.As per Orphan Drug Act amendment (1983) Act of USA, a rare disease /condition is one that affects less then 0.2 million people in USA. 4.India, like many developing countries, currently has no standard definition. Considering the large population of India, ORDI (Organization for Rare Diseases in India) suggests a disease to be defined as rare if it affects 1 in 5,000 people or less. 5.Sponsors have to first send request to the Office of Orphan Products Development (OOPD) to grant orphan designation to their drug or biological product to take advantage of financial incentives available for further product development then further go for review for designation request and finally approval for market product. 6.Government Body pay free of cost for these drug that is used for rare disease. 7.Recently,Risdiplam (Eversdy) drug give to child patient in J.K.LON Hospital to treat Spinal Muscular Atrophy free of cost which is rare disease. GOI self funded for this. 8.Sponsor collaborated with GOI and pharmaceutical companies for new approved orphan ,so these drugs should be easily accessible and affordable to patients with rare diseases in India.

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